Novel 6-bridged heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

ABSTRACT

The invention provides novel compounds having the general formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and R 4  are as defined in the description and in the claims, as well as or pharmaceutically acceptable salts, or tautomerism isomers, or enantiomers, or diastereomers thereof. The invention also contains compositions including the compounds and methods of using the compounds.

PRIORITY OF INVENTION

This application claims priority under 35 U.S.C. 119(a) and 35 U.S.C.365(a) to International Application Nos. PCT/CN2014/075392 filed on Apr.15, 2014 and to PCT/CN2013/075815 filed on May 17, 2013. The entirecontent of the applications referenced above are hereby incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a human, and in particular to Hepatitis B virus(HBV) inhibitors by targeting on HBV capsid for the treatment of HBVinfection.

HBV is a species of the hepadnaviridae family of viruses. HBV is aserious public health problem worldwide, with more than 400 millionpeople especially in Asia-pacific regions chronically infected by thissmall enveloped DNA virus. Although most individuals seem to resolve theinfection following acute symptoms, 15-40% of HBV patients will finallydevelop clinical diseases during their lifespan, most notably,hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year500,000 to 1 million people die from the end stage of liver diseasescaused by HBV infection.

HBV lifecycle begins with the binding of the “Dane” particle with anunidentified receptor on the surface of hepatocyte. Following entry,viral genome is delivered into nucleus where a covalently closedcircular DNA (cccDNA) is formed through DNA repair of viral relaxedcircular DNA. Unlike the mechanisms of most other DNA viruses, HBVcccDNA replicates through the retrotranscription of a 1.1-genomeunit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interactswith other two viral components, capsid protein and polymerase, as wellas some host factors, to form capsid particles where viral DNAreplication occurs. Most copies of the encapsidated genome thenefficiently associate with the envelope proteins for virion assembly andsecretion; a minority of these genomes is shunted to the nucleus, wherethey are converted to cccDNA.

Currently, there are two types of anti-HBV agents on the market,nucleoside (tide) analogs targeting viral polymerase (lamivudine,adefovir, tenofovir, telbivudine and entecavir) and interferonmodulating host immune functions. Mutations in the primary sequence ofthe polymerase that confer resistance to lamivudine and adefovir havebeen identified clinically and underlie a rebound of serum virus titersthat 70% of treated patients experience within 3 years of the start oflamivudine therapy. Although resistance to telbivudine, adefovir, andentecavir occurs more rarely, it has been recorded. Interferon alpha isthe other major therapy available for hepatitis B, but it is limited bya poor long-term response and debilitating side effects. Some viralgenotypes do not show good responses to interferon therapy. Now, thestandard of clinic cure of HBV infection is the loss and/orseroconversion of HBsAg. The majority (around or more than 90%) oftreated patients fail to achieve this goal. This drawback is mainly dueto the presence of a stable pool of viral cccDNA in nucleus that doesn'treplicate itself, therefore, shows no accessibility to nucleoside (tide)analogs.

Hence, there is certainly a medical need for treatments with improvedcharacteristics and for a diversity of approaches in the development oftherapies for HBV infection.

HBV capsid protein plays essential roles in HBV replication. HBV has anicosahedral core comprising of 240 copies of the capsid (or core)protein. The predominant biological function of capsid protein is to actas a structural protein to encapsidate pre-genomic RNA and form immaturecapsid particles in the cytoplasm. This step is prerequisite for viralDNA replication. The HBV capsid spontaneously self-assembles from manycopies of core dimers present in the cytoplasm. It has been shown thatthe formation of a trimeric nucleus and the subsequent elongationreactions occur by adding one dimeric subunit at a time until it iscomplete. Besides this function, capsid protein regulates viral DNAsynthesis through different phosphorylation status of its C-terminalphosphorylation sites. When a near full-length relaxed circular DNA isformed through reverse-transcription of viral pregenomic RNA, animmature capsid becomes a mature capsid. On one hand, capsid proteinmight facilitate the nuclear translocation of viral relaxed circulargenome by means of the nuclear localization signals located in theArginine-rich domain of the C-terminal region of capsid protein. Innucleus, as a component of viral cccDNA minichromosome, capsid proteincould play a structural and regulatory role in the functionality ofcccDNA minichromosomes. Capsid protein also interacts with viral largeenvelope protein in endoplasmic reticulum and triggers the release ofintact viral particles from hepatocytes.

There has been a couple of capsid related anti-HBV inhibitors reported.For example, phenylpropenamide derivatives, including compounds namedAT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), anda class of thiazolidin-4-ones from Valeant R&D (WO2006/033995), havebeen shown to inhibit pgRNA packaging. A recent study suggested thatphenylpropenamides are, in fact, accelerators of HBV capsid assembly,and their actions result in the formation of empty capsids. These veryinteresting results illustrate the importance of the kinetic pathway insuccessful virus assembly.

Heteroaryldihydropyrimidines or HAP, including compounds named Bay41-4109, Bay 38-7690 and Bay 39-5493, were discovered in a tissueculture-based screening (Deres K. et al. Science 2003, 893). These HAPanalogs act as synthetic allosteric activators and are able to induceaberrant capsid formation that leads to degradation of the core protein.HAP analogs also reorganized core protein from preassembled capsids intononcapsid polymers, presumably by interaction of HAP with dimers freedduring capsid ‘breathing’, the transitory breaking of individualintersubunit bonds. Bay 41-4109 was administered to HBV infectedtransgenic mouse or humanized mouse models and demonstrated in vivoefficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893;Brezillon N. et al. PLoS ONE 2011, e25096). It was also shown thatbis-ANS, a small molecule that acts as a molecular ‘wedge’ andinterferes with normal capsid-protein geometry and capsid formation(Zlotnick A. et al. J. Virol. 2002, 4848-4854).

SUMMARY OF THE INVENTION

Objects of the present invention are novel compounds of formula I, theirmanufacture, medicaments based on a compound in accordance with theinvention and their production as well as the use of compounds offormula I for the treatment or prophylaxis of HBV infection.

In one aspect the present invention provides for compounds of formula(I)

wherein, R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen or C₁₋₆alkyl; R³ is hydrogen or C₁₋₆alkyl;R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and the otherone is hydrogen, halogen or hydroxy; one of R^(5b) and R^(6b) ishydrogen or halogen, and the other one is hydrogen or halogen; R⁹ ishydrogen or carboxy; one of R¹⁷ and R¹⁸ is hydrogen, halogen, hydroxy,amino, C₁₋₆alkylsulfonylamino or trifluoromethylcarbonylamino, the otherone is hydrogen, halogen, hydroxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-O—,C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—O—,carboxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-NH—, C₁₋₆alkylsulfonyl-NH—,aminocarbonyl-NH— or aminosulfonyl-NH—; wherein —C_(y)H_(2y)— isunsubstituted once or more times substituted by hydroxy; or R^(6a) andR¹⁷ together with the carbon atoms, to which they are attached, form aring of isoxazolyl, pyrazolyl or oxo-dihydropyrazolyl, which ring isunsubstituted or once or more times substituted by C₁₋₆alkyl; or R¹⁷ andR¹⁸ together with the carbon atom, to which they are attached, formdiazirinyl; X is oxygen; sulfur; —(carbonylC₁₋₆alkyl)-; or —C(R¹⁵R¹⁶)—,wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the other one ishydrogen or carboxy-C_(y)H_(2y)—; r is 0 or 1; m is 0 or 1; n is 0 or 1;y is 0-6; or R⁴ is

wherein R⁷ is hydrogen or halogen; R⁸ is hydrogen or halogen; R¹⁰ ishydrogen, halogen, hydroxy-C_(y)H_(2y)— orC₁₋₆alkylcarbonylamino-C_(y)H_(2y)—; R¹¹ is hydrogen or carboxy; R¹² ishydrogen or carboxy; W is a bond, oxygen, —CH₂—, —CF₂— or—N(carbonylC₁₋₆alkyl)-; t is 1 or 2; y is 0-6;with the proviso that

is excluded;

or R⁴ is

wherein R¹⁹ is hydrogen; C₁₋₆alkyl, which is unsubstituted or once ormore times substituted by halogen; C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—;hydroxy-C_(y)H_(2y)-carbonyl; carboxy-C_(y)H_(2y)-carbonyl;C₁₋₆alkylaminosulfonyl; C₁₋₆alkylcarbonyl; C₁₋₆ alkylsulfonyl;aminocarbonyl; or aminosulfonyl; Y is carbonyl or —CH₂—; u is 0 or 1; yis 0-6;

or R⁴ is

wherein M is a bond, —CH₂— or —N(R¹⁴)—CH₂—; K is C₁₋₆alkoxycarbonyl; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.

In another aspect, the present invention provides for methods ofpreparing compounds of Formula (I)

In another aspect the present invention provides for the use ofcompounds of formula (I) for the treatment or prophylaxis of HBVinfection.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “C₁₋₆alkyl” alone or in combination signifies asaturated, linear- or branched chain alkyl group containing 1 to 6,particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl,isopropyl, 1-butyl, 2-butyl, tert-butyl and the like. Particular“C₁₋₆alkyl” groups are methyl, ethyl, isopropyl and tert-butyl.

The term “cycloalkyl”, alone or in combination, refers to a saturatedcarbon ring containing from 3 to 7 carbon atoms, particularly from 3 to6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like. Particular “cycloalkyl” groups arecyclopropyl, cyclopentyl and cyclohexyl.

The term “—C_(x)H_(2x)-” alone or in combination signifies a saturated,linear or branched chain alkyl group containing from 1 to 6 carbonatoms, particularly from 1 to 4 carbon atoms.

The term “—C_(y)H_(2y)-” alone or in combination signifies a chemicallink or a saturated, linear or branched chain alkyl group containingfrom 1 to 6 carbon atoms, particularly, the term signifies a chemicallink or a saturated, linear or branched chain alkyl group containingfrom 1 to 4 carbon atoms.

The term “C₁₋₆alkoxy” alone or in combination signifies a groupC₁₋₆alkyl-O—, wherein the “C₁₋₆alkyl” is as defined above; for examplemethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy,t-butoxy and the like. Particular C₁₋₆alkoxy groups are methoxy andethoxy and more particularly methoxy.

The term “amino”, alone or in combination, refers to primary (—NH₂),secondary (—NH—) or tertiary amino

The term “carboxy” alone or in combination refers to the group —COOH.

The term “cyano” alone or in combination refers to the group —CN.

The term “halogen” means fluorine, chlorine, bromine or iodine. Halogenis particularly fluorine, chlorine or bromine.

The term “hydroxy” alone or in combination refers to the group —OH.

The term “sulfonyl” alone or in combination refers to the group —S(O)₂—.

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “carboxy-C_(y)H_(2y)-” refers to a group “—C_(y)H_(2y)—COOH”,wherein the “—C_(y)H_(2y)-” is as defined above.

The term “hydroxy-C_(y)H_(2y)-” refers to a group “—C_(y)H_(2y)—OH”,wherein the “—C_(y)H_(2y)-” is as defined above.

The term “C₁₋₆alkoxycarbonyl” refers to a group C₁₋₆alkoxy-C(O)—,wherein the “C₁₋₆alkoxy” is as defined above.

The term “C₁₋₆alkylcarbonyl” refers to a group C₁₋₆alkyl-C(O)—, whereinthe “C₁₋₆alkyl” is as defined above.

The term “aminocarbonyl” refers to a group amino-C(O)—, wherein the“amino” is as defined above.

The term “C₁₋₆alkylsulfonyl” refers to a group C₁₋₆alkyl-S(O)₂—, whereinthe “C₁₋₆alkyl” is as defined above.

The term “aminosulfonyl” refers to a group amino-S(O)₂—, wherein the“amino” is as defined above.

The term “tautomerism isomers” refers to constitutional isomers oforganic compounds that readily interconvert by a chemical reactioncalled tautomerization. This reaction commonly results in the formalmigration of a hydrogen atom or proton, accompanied by a switch of asingle bond and adjacent double bond. For example, compounds of generalformula (I)

and its tautomerism isomer

The term “enantiomer” denotes two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “diastereomer” denotes a stereoisomer with two or more centersof chirality and whose molecules are not mirror images of one another.

The compounds according to the present invention may exist in the formof their pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of formula I and are formed from suitablenon-toxic organic or inorganic acids or organic or inorganic bases.Acid-addition salts include for example those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluenesulfonic acid, salicylicacid, methanesulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, and the like. Base-addition saltsinclude those derived from ammonium, potassium, sodium and, quaternaryammonium hydroxides, such as for example, tetramethyl ammoniumhydroxide. The chemical modification of a pharmaceutical compound into asalt is a technique well known to pharmaceutical chemists in order toobtain improved physical and chemical stability, hygroscopicity,flowability and solubility of compounds. It is for example described inBastin R. J., et al., Organic Process Research & Development 2000, 4,427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms andDrug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particularare the sodium salts of the compounds of formula I.

Compounds of the general formula I which contain one or several chiralcenters can either be present as racemates, diastereomeric mixtures, oroptically active single isomers. The racemates can be separatedaccording to known methods into the enantiomers. Particularly,diastereomeric salts which can be separated by crystallization areformed from the racemic mixtures by reaction with an optically activeacid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid,lactic acid or camphorsulfonic acid.

Inhibitors of HBV

The present invention provides (i) novel compounds having the generalformula I:

wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen, halogen or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen or halogen, and the            other one is hydrogen or halogen;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, halogen, hydroxy, amino,            C₁₋₆alkylsulfonylamino or trifluoromethylcarbonylamino, the            other one is hydrogen, halogen, hydroxy-C_(y)H_(2y)—,            C₁₋₆alkylcarbonyl-O—, C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—,            carboxy-C_(y)H_(2y)—O—, carboxy-C_(y)H_(2y)—, C₁₋₆            alkylcarbonyl-NH—, C₁₋₆alkylsulfonyl-NH—, aminocarbonyl-NH—            or aminosulfonyl-NH—;            -   wherein —C_(y)H_(2y)— is unsubstituted once or more                times substituted by hydroxy;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of isoxazolyl, pyrazolyl or            oxo-dihydropyrazolyl, which ring is unsubstituted or once or            more times substituted by C₁₋₆alkyl;        -   or R¹⁷ and R¹⁸ together with the carbon atom, to which they            are attached, form diazirinyl;        -   X is oxygen; sulfur; —(carbonylC₁₋₆alkyl)-; or —C(R¹⁵R¹⁶)—,            wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the            other one is hydrogen or carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen or halogen;        -   R⁸ is hydrogen or halogen;        -   R¹⁰ is hydrogen, halogen, hydroxy-C_(y)H_(2y)— or            C₁₋₆alkylcarbonylamino-C_(y)H_(2y)—;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen, —CH₂—, —CF₂— or —N(carbonylC₁₋₆alkyl)-;        -   t is 1 or 2;        -   y is 0-6;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydrogen; C₁₋₆alkyl, which is unsubstituted            or once or more times substituted by halogen;            C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—;            hydroxy-C_(y)H_(2y)-carbonyl; carboxy-C_(y)H_(2y)-carbonyl;            C₁₋₆ alkylaminosulfonyl; C₁₋₆ alkylcarbonyl;            C₁₋₆alkylsulfonyl; aminocarbonyl; or aminosulfonyl;        -   Y is carbonyl or —CH₂—;        -   u is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein M is a bond, —CH₂— or —N(R¹⁴)—CH₂—;        -   R¹⁴ is C₁₋₆alkoxycarbonyl;            or pharmaceutically acceptable salts, or tautomerism            isomers, or enantiomers, or diastereomers thereof.

Another embodiment of present invention is (ii) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen, fluoro or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen or fluoro, and the            other one is hydrogen or fluoro;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, fluoro, hydroxy, amino,            methylsulfonylamino or trifluoromethylcarbonylamino, the            other one is hydrogen, fluoro, hydroxy, hydroxymethyl,            methylcarbonyl-O—, methoxycarbonyl, methoxycarbonylmethyl,            ethoxycarbonylmethyl, methoxycarbonyl(hydroxy)methyl,            ethoxycarbonyl(hydroxy)methyl, carboxymethyl-O—, carboxy,            carboxymethyl, methylcarbonylamino, aminocarbonylamino,            methylsulfonylamino or aminosulfonylamino;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of isoxazolyl, pyrazolyl or            oxo-dihydropyrazolyl, which ring is unsubstituted or once or            more times substituted by methyl;        -   or R¹⁷ and R¹⁸ together with the carbon atom, to which they            are attached, form diazirinyl;        -   X is oxygen; sulfur; —N(carbonylmethyl)-; or —C(R¹⁵R¹⁶)—,            wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the            other one is hydrogen, carboxy or carboxymethyl;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen or fluoro;        -   R⁸ is hydrogen or fluoro;        -   R¹⁰ is hydrogen, fluoro, hydroxymethyl or            methylcarbonylaminomethyl;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen, —CH₂—, —CF₂— or —N(carbonylmethyl)-;        -   t is 1 or 2;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydrogen, methyl, isopropyl,            difluoromethylmethyl, methylcarbonyl, methoxycarbonyl,            ethoxycarbonylisopropyl, hydroxymethylcarbonyl,            carboxyisopropylcarbonyl, aminocarbonyl, methylsulfonyl,            aminosulfonyl or methylaminosulfonyl;        -   Y is carbonyl or —CH₂—;        -   u is 0 or 1;

    -   or R⁴ is

-   -   -   wherein M is a bond, —CH₂— or —N(carbonyltert-butoxy)-CH₂—;            or pharmaceutically acceptable salts, or tautomerism            isomers, or enantiomers, or diastereomers thereof.

Another embodiment of present invention is (iii) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen or halogen;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen or C₁₋₆alkylsulfonylamino,            the other one is hydrogen, C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—,            carboxy-C_(y)H_(2y)—O—, carboxy-C_(y)H_(2y)—,            C₁₋₆alkylcarbonyl-NH—, C₁₋₆alkylsulfonyl-NH— or            aminosulfonyl-NH—;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form pyrazolyl;        -   X is oxygen; sulfur; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and            R¹⁶ is hydrogen or hydroxy, and the other one is hydrogen or            carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6.

Further embodiment of present invention is (iv) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen or fluoro;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen or methylsulfonylamino, the            other one is hydrogen, ethoxycarbonylmethyl,            carboxymethyl-O—, carboxy, carboxymethyl,            methylcarbonyl-NH—, methylsulfonyl-NH— or aminosulfonyl-NH—;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form pyrazolyl;        -   X is oxygen; sulfur; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and            R¹⁶ is hydrogen or hydroxy, and the other one is hydrogen,            carboxy or carboxymethyl;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1.

Another embodiment of present invention is (v) a compound of formula IA

wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   one of R^(5a) and R^(6a) is hydrogen or halogen, and the other        one is hydrogen, halogen or hydroxy;    -   R¹⁷ is hydrogen or amino;    -   p is 0 or 1;        or pharmaceutically acceptable salts, or tautomerism isomers, or        enantiomers, or diastereomers thereof.

Further embodiment of present invention is (vi) a compound of formula IAor a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   one of R^(5a) and R^(6a) is hydrogen or fluoro, and the other        one is hydrogen, fluoro or hydroxy;    -   R¹⁷ is hydrogen or amino;    -   p is 0 or 1.

Another embodiment of present invention is (vii) a compound of formulaIB

wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen;    -   R¹⁵ is hydrogen or hydroxy;    -   q is 0 or 1;        or pharmaceutically acceptable salts, or tautomerism isomers, or        enantiomers, or diastereomers thereof.

Another embodiment of present invention is (viii) a compound of formulaIB or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen;    -   R¹⁵ is hydrogen or hydroxy;    -   q is 0 or 1.

Another embodiment of present invention is (ix) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein R¹⁹ is hydrogen, aminocarbonyl, aminosulfonyl or            hydroxy-C_(y)H_(2y)-carbonyl;        -   Y is —CH₂— or carbonyl;        -   j is 0 or 1;        -   y is 0-6.

Further embodiment of present invention is (x) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro or chloro;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein R¹⁹ is hydrogen, aminocarbonyl, aminosulfonyl or            hydroxymethylcarbonyl;        -   Y is —CH₂— or carbonyl;        -   j is 0 or 1.

Another embodiment of present invention is (xi) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen or halogen;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, the other one is hydrogen or            carboxy-C_(y)H_(2y)—;        -   X is oxygen; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is            hydrogen or hydroxy, and the other one is hydrogen or            carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 1;        -   n is 0 or 1;        -   y is 0-6.

Another embodiment of present invention is (xii) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro or chloro;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen or fluoro;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, the other one is hydrogen or            carboxymethyl;        -   X is oxygen; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is            hydrogen or hydroxy, and the other one is hydrogen or            carboxymethyl;        -   r is 0 or 1;        -   m is 1;        -   n is 0 or 1.

Another embodiment of present invention is (xiii) a compound of formulaI or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen, halogen or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen, and the other one is            hydrogen or carboxy-C_(y)H_(2y)—;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen or amino, the other one is            hydrogen, carboxy-C_(y)H_(2y)—O—, carboxy-C_(y)H_(2y)—,            C₁₋₆alkylcarbonyl-NH—, C₁₋₆ alkylsulfonyl-NH—,            aminocarbonyl-NH— or aminosulfonyl-NH—;        -   X is oxygen; —N(carbonylC₁₋₆alkyl)- or —C(R¹⁵R¹⁶)—, wherein            one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the other one            is hydrogen or carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydrogen, halogen or hydroxy-C_(y)H_(2y)—;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen or —CH₂—;        -   t is 1 or 2;        -   y is 0-6;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydroxy-C_(y)H_(2y)-carbonyl,            carboxy-C_(y)H_(2y)-carbonyl, C₁₋₆alkylsulfonyl,            aminocarbonyl or aminosulfonyl;        -   y is 0-6.

Further embodiment of present invention is (xiv) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen, fluoro or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen, and the other one is            hydrogen or carboxymethyl;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen or amino, the other one is            hydrogen, carboxy, carboxymethyl, carboxymethyl-O—,            methylcarbonylamino, aminocarbonylamino, methylsulfonylamino            or aminosulfonylamino;        -   X is oxygen; —N(carbonylmethyl)-; or —C(R¹⁵R¹⁶)—, wherein            one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the other one            is hydrogen, carboxy, or carboxymethyl;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydrogen, fluoro or hydroxymethyl;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen or —CF₂—;        -   t is 1 or 2.        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydroxymethylcarbonyl,            carboxyisopropylcarbonyl, aminocarbonyl, methylsulfonyl or            aminosulfonyl.

Another embodiment of present invention is (xv) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen, halogen or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen or halogen, and the            other one is hydrogen or halogen;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, hydroxy or amino, the other            one is hydroxy-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—O—,            carboxy-C_(y)H_(2y)—, or C₁₋₆alkylcarbonyl-NH—;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of oxo-dihydropyrazolyl,            which ring is unsubstituted or once or more times            substituted by C₁₋₆alkyl;        -   X is oxygen; sulfur; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and            R¹⁶ is hydrogen, and the other one is hydrogen or            carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydrogen, halogen, hydroxy-C_(y)H_(2y)— or            C₁₋₆alkylcarbonylamino-C_(y)H_(2y)—;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen, —CF₂—, or —N(carbonylC₁₋₆alkyl)-;        -   t is 1 or 2;        -   y is 0-6;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydrogen, C₁₋₆alkyl,            hydroxy-C_(y)H_(2y)-carbonyl, carboxy-C_(y)H_(2y)-carbonyl,            C₁₋₆alkylcarbonyl or aminocarbonyl;        -   Y is carbonyl or —CH₂—;        -   u is 0 or 1;        -   y is 0-6.

Further embodiment of present invention is (xvi) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen, fluoro or hydroxy;        -   one of R^(5b) and R^(6b) is hydrogen or fluoro, and the            other one is hydrogen or fluoro;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, hydroxy or amino, the other            one is hydroxy, carboxymethyl-O—, carboxy, carboxymethyl or            methylcarbonylamino;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of oxo-dihydropyrazolyl,            which ring is unsubstituted or once or more times            substituted by methyl;        -   X is oxygen; sulfur; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and            R¹⁶ is hydrogen, and the other one is hydrogen            carboxymethyl;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydrogen, fluoro, hydroxymethyl or            methylcarbonylaminomethyl;        -   R¹¹ is hydrogen or carboxy;        -   R¹² is hydrogen or carboxy;        -   W is a bond, oxygen, —CF₂—, or —N(carbonylmethyl)-;        -   t is 1 or 2;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is hydrogen, methyl, isopropyl, methylcarbonyl,            hydroxymethylcarbonyl, carboxyisopropylcarbonyl or            aminocarbonyl;        -   Y is carbonyl or —CH₂—;        -   u is 0 or 1.

Another embodiment of present invention is (xvii) a compound of formulaI or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen or halogen;        -   one of R^(5b) and R^(6b) is hydrogen or halogen, and the            other one is hydrogen or halogen;        -   R⁹ is hydrogen or carboxy; one of R¹⁷ and R¹⁸ is hydrogen,            halogen, hydroxy, C₁₋₆alkylsulfonylamino or            trifluoromethylcarbonylamino, the other one is hydrogen,            halogen, hydroxy-C_(y)H_(2y)—,            C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—,            C₁₋₆alkylcarbonyl-NH—, C₁₋₆ alkylsulfonyl-NH—,            aminocarbonyl-NH— or aminosulfonyl-NH—;            -   wherein —C_(y)H_(2y)— is unsubstituted once or more                times substituted by hydroxy;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of isoxazolyl, pyrazolyl or            oxo-dihydropyrazolyl, which ring is unsubstituted or once or            more times substituted by C₁₋₆alkyl;        -   or R¹⁷ and R¹⁸ together with the carbon atom, to which they            are attached, form diazirinyl;        -   X is oxygen; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is            hydrogen or hydroxy, and the other one is            carboxy-C_(y)H_(2y)—;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydroxy-C_(y)H_(2y)—;        -   R¹¹ is hydrogen;        -   R¹² is hydrogen;        -   W is oxygen;        -   t is 1;        -   y is 0-6;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is C₁₋₆alkyl, which is unsubstituted or once or            more times substituted by halogen;            C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkylsulfonyl;            aminocarbonyl; or aminosulfonyl;        -   Y is —CH₂—;        -   u is 0;        -   y is 0-6;

    -   or R⁴ is

-   -   wherein M is a bond or —CH₂—.

Further embodiment of present invention is (xviii) a compound of formulaI or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro, bromo or methyl;    -   R³ is hydrogen or methyl;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen or fluoro;        -   one of R^(5b) and R^(6b) is hydrogen or fluoro, and the            other one is hydrogen or fluoro;        -   R⁹ is hydrogen or carboxy;        -   one of R¹⁷ and R¹⁸ is hydrogen, fluoro, hydroxy,            methylsulfonylamino or trifluoromethylcarbonylamino, the            other one is hydrogen, fluoro, hydroxy, hydroxymethyl,            methoxycarbonylmethyl, ethoxycarbonylmethyl,            ethoxycarbonyl(hydroxy)methyl, carboxy, carboxymethyl,            methylcarbonylamino, aminocarbonylamino, methylsulfonylamino            or aminosulfonylamino;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form a ring of isoxazolyl, pyrazolyl or            oxo-dihydropyrazolyl, which ring is unsubstituted or once or            more times substituted by methyl;        -   or R¹⁷ and R¹⁸ together with the carbon atom, to which they            are attached, form diazirinyl;        -   X is oxygen; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is            hydrogen or hydroxy, and the other one is carboxy or            carboxymethyl;        -   r is 0 or 1;        -   m is 0 or 1;        -   n is 0 or 1;

    -   or R⁴ is

-   -   -   wherein R⁷ is hydrogen;        -   R⁸ is hydrogen;        -   R¹⁰ is hydrogen, or hydroxymethyl;        -   R¹¹ is hydrogen;        -   R¹² is hydrogen;        -   W is oxygen;        -   t is 1;        -   with the proviso that

-   -   -   -   is excluded;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is difluoromethylmethyl, methoxycarbonyl,            aminocarbonyl, methylsulfonyl or aminosulfonyl;        -   Y is —CH₂—;        -   u is 0;

    -   or R⁴ is

-   -   wherein M is a bond or —CH₂—.

Another embodiment of present invention is (xix) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and            the other one is hydrogen or halogen;        -   one of R¹⁷ and R¹⁸ is hydrogen, the other one is hydrogen,            carboxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-NH— or            aminosulfonyl-NH—;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form pyrazolyl;        -   X is oxygen or —C(carboxyC₁₋₆alkyl)-;        -   m is 0 or 1;        -   n is 0 or 1;        -   y is 0-6;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is C₁₋₆alkyl;

    -   or R⁴ is

Further embodiment of present invention is (xx) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro or bromo;    -   R³ is hydrogen;    -   R⁴ is

-   -   -   wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and            the other one is hydrogen or fluoro;        -   one of R¹⁷ and R¹⁸ is hydrogen, the other one is hydrogen,            carboxymethyl, methylcarbonylamino or aminosulfonylamino;        -   or R^(6a) and R¹⁷ together with the carbon atoms, to which            they are attached, form pyrazolyl;        -   X is oxygen or —C(carboxymethyl)-;        -   m is 0 or 1;        -   n is 0 or 1;

    -   or R⁴ is

-   -   -   wherein R¹⁹ is methyl;

    -   or R⁴ is

Another embodiment of present invention is (xxi) a compound of formulaIC, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is selected from

-   -   wherein R¹⁰ is hydroxy-C_(y)H_(2y)—;    -   R¹³ is C₁₋₆alkylcarbonyl;    -   R¹⁴ is C₁₋₆alkoxycarbonyl;    -   X is —O— or —S—; provided that    -   when X is —O—, R¹⁷ is hydrogen or hydroxy, R¹⁸ is        C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—,        hydroxy-C_(y)H_(2y)—, C₁₋₆ alkylcarbonyl-O—, C₁₋₆        alkylcarbonylamino, C₁₋₆alkylsulfonylamino or

-   -   -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they            are attached, form

-   -   when X is —S—, R¹⁷ is hydrogen, R¹⁸ is carboxy-C_(y)H_(2y)—;    -   R¹⁹ is selected from aminocarbonyl; aminosulfonyl;        C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkyl, which is        unsubstituted or substituted by fluoro; C₁₋₆alkylaminosulfonyl;        C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl and        hydroxy-C_(x)H_(2x)-carbonyl;    -   A is pyrazolyl or oxopyrazolyl, which is unsubstituted or        substituted by C₁₋₆alkyl;    -   x is 1-6;    -   y is 0-6;        or pharmaceutically acceptable salts, or tautomerism isomers, or        enantiomers, or diastereomers thereof.

Further embodiment of present invention is (xxii) a compound of formulaIC, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro or bromo;    -   R³ is hydrogen or methyl;    -   R⁴ is selected from

-   -   wherein R¹⁷ is hydrogen or hydroxy;    -   R¹⁸ is methoxycarbonyl, methoxycarbonylmethyl,        methoxycarbonylmethyl(hydroxy), carboxy, carboxymethyl, hydroxy,        hydroxymethyl, methylcarbonyl-O—, methylcarbonylamino or        methylsulfonylamino;    -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they are        attached, form

-   -   R¹⁹ is aminocarbonyl, aminosulfonyl, methoxycarbonyl,        ethoxycarbonylisopropyl, methyl, isopropyl, difluoroethyl,        methylaminosulfonyl, methylcarbonyl, methylsulfonyl or        hydroxymethylcarbonyl;    -   A is pyrazolyl or oxopyrazolyl, which is unsubstituted or        substituted by methyl; or pharmaceutically acceptable salts, or        tautomerism isomers, or enantiomers, or diastereomers thereof.

Another embodiment of present invention is (xxiii) a compound of formulaIC, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen;    -   R⁴ is selected from

-   -   wherein R¹⁰ is hydroxy-C_(x)H_(2x)—;    -   R¹⁷ is hydrogen, R¹⁸ is C₁₋₆alkoxycarbonyl,        carboxy-C_(x)H_(2x)—, hydroxy, C₁₋₆alkylcarbonylamino,        C₁₋₆alkylsulfonylamino or

-   -   -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they            are attached, form

-   -   R¹⁹ is selected from aminocarbonyl; aminosulfonyl;        C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkyl, which is        unsubstituted or substituted by fluoro; C₁₋₆alkylaminosulfonyl;        C₁₋₆alkylcarbonyl; and hydroxy-C_(x)H_(2x)-carbonyl;    -   A is C₁₋₆alkylpyrazolyl;    -   x is 1-6;    -   y is 0-6;        or pharmaceutically acceptable salts, or tautomerism isomers, or        enantiomers, or diastereomers thereof.

Further embodiment of present invention is (xxiv) a compound of formulaIC, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro or bromo;    -   R³ is hydrogen;    -   R⁴ is selected from

-   -   wherein R¹⁷ is hydrogen;    -   R¹⁸ is methoxycarbonyl, methoxycarbonylmethyl(hydroxy),        carboxymethyl, hydroxy, methylcarbonylamino or        methylsulfonylamino;    -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they are        attached, form

-   -   R¹⁹ is aminocarbonyl, aminosulfonyl, methoxycarbonyl,        ethoxycarbonylisopropyl, methyl, difluoroethyl,        methylaminosulfonyl, methylcarbonyl, or hydroxymethylcarbonyl;        or pharmaceutically acceptable salts, or tautomerism isomers, or        enantiomers, or diastereomers thereof.

Another embodiment of present invention is (xxv) a compound of formulaIC or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is selected from

-   -   X is —O— or —S—; provided that    -   when X is —O—, R¹⁷ is hydrogen or hydroxy, R¹⁸ is        C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—,        hydroxy-C_(y)H_(2y)—, C₁₋₆ alkylcarbonyl-O—, C₁₋₆        alkylcarbonylamino, C₁₋₆alkylsulfonylamino or

-   -   -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they            are attached, form

-   -   when X is —S—, R¹⁷ is hydrogen, R¹⁸ is carboxy-C_(y)H_(2y)—;    -   R¹⁹ is selected from aminocarbonyl; aminosulfonyl;        C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkyl, which is        unsubstituted or substituted by fluoro; C₁₋₆alkylaminosulfonyl;        C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl and        hydroxy-C_(x)H_(2x)-carbonyl;    -   A is pyrazolyl or oxopyrazolyl, which is unsubstituted or        substituted by C₁₋₆alkyl;    -   x is 1-6;    -   y is 0-6.

Further embodiment of present invention is (xxvi) a compound of formulaIC or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl or ethyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro or bromo;    -   R³ is hydrogen or methyl;    -   R⁴ is selected from

-   -   R¹⁷ is hydrogen or hydroxy;    -   R¹⁸ is methoxycarbonyl, methoxycarbonylmethyl,        methoxycarbonylmethyl(hydroxy), carboxy, carboxymethyl, hydroxy,        hydroxymethyl, methylcarbonyl-O—, methylcarbonylamino or        methylsulfonylamino;    -   or R¹⁷ and R¹⁸, together with the carbon atom, to which they are        attached, form

-   -   R¹⁹ is aminocarbonyl, aminosulfonyl, methoxycarbonyl,        ethoxycarbonylisopropyl, methyl, isopropyl, difluoroethyl,        methylaminosulfonyl, methylcarbonyl, methylsulfonyl or        hydroxymethylcarbonyl;    -   A is pyrazolyl or oxopyrazolyl, which is unsubstituted or        substituted by methyl.

Another embodiment of present invention is (xxvii) a compound of formulaIC or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof, wherein

-   -   R¹ is C₁₋₆alkyl;    -   R² is phenyl, which is once or twice or three times substituted        by halogen;    -   R³ is hydrogen;    -   R⁴ is

Further embodiment of present invention is (xxviii) a compound offormula IC or a pharmaceutically acceptable salt or tautomerism isomersor enantiomers or diastereomers thereof, wherein

-   -   R¹ is methyl;    -   R² is phenyl, which is once or twice or three times substituted        by fluoro, chloro or bromo;    -   R³ is hydrogen;    -   R⁴ is

Particular compounds of formula I, including their activity data, NMRdata and MS data are summarized in the following Table 1 and 2.

Particular compounds of formula I include the following:

-   9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   9-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid;-   9-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid;-   9-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid methyl ester;-   9-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid;-   8-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylic    acid;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Acetoxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methylsulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   9-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic    acid methyl ester;-   (R)-6-(7-Carbamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-sulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(1-ethoxycarbonyl-1-methyl-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2-hydroxy-acetyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   7-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic    acid tert-butyl ester;-   (S)-2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-5,5-difluoro-2-aza-bicyclo[2.2.2]octane-3-carboxylic    acid;-   (R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Bromo-4-fluoro-phenyl)-6-(7-carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5-methyl-3-oxo-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6)-en-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-10-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(2-methoxymethyl-azetidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(6-oxa-3-aza-bicyclo[3.1.1]hept-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-3-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3,6-diaza-bicyclo[3.2.1]octane-7-carboxylic    acid;-   2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic    acid;-   (R)-6-(5-Acetyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-(7-Carboxymethyl-3-thia-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Diazirine-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-((1R,3R,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(9-oxa-3,4,11-triaza-tricyclo[5.3.1.0*2,6*]undeca-2(6),4-dien-11-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   2-[[(1R,5S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]acetic    acid;-   2-[[(1R,5S)-9-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]acetic    acid;-   Methyl    (4R)-6-[(6-acetamido-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   2-[[8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]oxy]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylic    acid;-   Methyl    (4R)-4-(2-bromo-4-fluoro-phenyl)-6-[[7-(2-hydroxyacetyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-bromo-4-fluoro-phenyl)-6-[(7-carbamoyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   2-[(1R,5S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-endo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-endo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate;-   2-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-exo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   2-[(1R,5S,6S)-8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]acetic    acid;-   Endo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Ethyl    (4R)-6-[[(1S,5R)-7-endo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   3-[(1S,5R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl]-2,2-dimethyl-3-oxo-propanoic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   (1S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   (1R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   (1S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   (1R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   (4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4,10-dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carrboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7,7-difluoro-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-arboxylic    acid methyl ester;-   Methyl    (4R)-4-(2-chloro-4-fluorophenyl)-6-[(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate;-   2-[(1R,3R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3R,5S)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid or 2-[(1 S,3    S,5R)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4S)-4-(3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   Methyl    (4R)-6-[(3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7S)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(1R,5R,7S)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid or    2-[(1S,5S,7R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(1R,5R,7S)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid or    2-[(1S,5S,7R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Endo-2-[9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Endo-2-[9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Endo-2-[9-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   7-amino-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   7-amino-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   7-amino-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-3-azabicyclo[2.2.1]heptan-3-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[4-(acetamidomethyl)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-[(2,2,2-trifluoroacetyl)amino]-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   (1S,4R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylic    acid;-   (1R,4S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylic    acid;-   8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   (5S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylic    acid; and-   (5R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylic    acid.

TABLE 1 NMR and MS data of particular compounds Example No. ¹H NMR dataMW data 1 ¹H NMR (CDCl₃, 400 MHz): 10.0 (br s, 1H), 7.88 (d, J = 3.0LC/MS: calc'd Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.27 (m, 1H), 7.15 (dd,J = 535 (MH⁺), exp 2.4, 8.5 Hz, 1H), 6.94 (m, 1H), 6.22 (s, 1H), 4.50(m, 2H), 4.23 535 (MH⁺) (s, 2H), 3.95 (m, 2H), 3.85 (m, 1H), 3.63 ( s,3H), 2.83 (m, 2H), 2.33 (m, 2H), 2.05 (m, 2 H). 2 ¹H NMR (METHANOL-d4,400 MHz): 7.41 (dd, J = 8.7, 6.1 LC/MS: calc'd Hz, 1H), 7.32 (d, J = 1Hz, 1H), 7.24 (dd, J = 8.8, 2.8 Hz, 1H), 549 (MH⁺), exp 7.04 (m, 1H),6.16 (s, 1H), 4.62 (d, J = 17.8 Hz, 1H), 4.08-4.23 549 (MH⁺) (m, 3H),3.92 (m, 2H), 3.71 (m, 1H), 3.63 (s, 3H), 2.88 (m, 1H), 2.83 (m, 1H),2.49 (d, J = 0.8 Hz, 3H), 2.30 (m, 2H), 2.04 (m, 2 H). 3 ¹H NMR(METHANOL-d4, 400 MHz): 8.01 (d, J = 3.3 Hz, LC/MS: calc'd 1H), 7.80 (d,J = 3.3 Hz, 1H), 7.13-7.27 (m, 3H), 5.73 (s, 1H), 519 (MH⁺), exp 4.54(d, J = 17.8 Hz, 1H), 4.14 (m, 2H), 4.01 (d, J = 17.8 Hz, 519 (MH⁺) 1H),3.81-3.96 (m, 2H), 3.72 (s, 3H), 3.64 (m, 1H), 2.78 (m, 1H), 2.68 (m,1H), 2.22 (m, 2H), 1.93 (m, 2 H). 4 ¹H NMR (DMSO-d6, 400 MHz):9.84-10.20 (m, 1H), 7.99- LC/MS: calc'd 8.07 (m, 1H), 7.95 (d, J = 3.3Hz, 1H), 7.57 (dd, J = 8.7, 2.64 593&595 (MH⁺), Hz, 1H), 7.39 (dd, J =8.7, 6.15 Hz, 1H), 7.20 (td, J = 8.5, 2.64 exp 593&595 Hz, 1H), 6.02 (s,1H) 4.35 (d, J = 17.6 Hz, 1H), 4.02-4.13 (m, (MH⁺) 1H), 3.79-3.98 (m,4H), 3.64 (s, 3H), 3.59 (t, J = 5.8 Hz, 1H), 3.53 (s, 3H), 2.82 (m, 1H),2.64-2.72 (m, 1H), 1.95-2.13 (m, 2H), 1.83 (td, J = 13.2, 5.1 Hz, 2 H).5 ¹H NMR (METHANOL-d4, 400 MHz): 7.96 (d, J = 3.3 Hz, LC/MS: calc'd 1H),7.75 (d, J = 3.0 Hz, 1H), 7.35-7.47 (m, 2H), 7.09 (td, J = 579&581(MH⁺), 8.4, 2.8 Hz, 1H), 6.16 (s, 1H), 4.56 (d, J = 17.6 Hz, 1H), 4.04-exp 579&581 4.21 (m, 3H), 3.86-3.97 (m, 2H), 3.65-3.74 (m, 1H), 3.60 (s,(MH⁺) 3H), 2.84 (m, 1H), 2.73 (m, 1H), 2.25 (d, J = 12.3 Hz, 2H), 1.89-2.03 (m, 2 H). 6 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.1 Hz,LC/MS: calc'd 0.5H), 7.97 (d, J = 3.1 Hz, 0.5H), 7.77 (d, J = 3.0 Hz,1H), 7.44 521 (MH⁺), exp (m, 1H), 7.24 (dd, J = 8.8, 2.8 Hz, 1H), 7.06(td, J = 8.4, 2.8 Hz, 521 (MH⁺) 1H), 6.18 (s, 0.5H), 6.18 (s, 0.5H),4.20 (m, 1H), 3.88-4.07 (m, 4H), 3.68 (m, 1H), 3.61 (s, 3H), 3.47 (m,2H), 3.31 (m, 1H), 2.48 (m, 1H), 2.36 (m, 1H). 7 ¹H NMR (METHANOL-d4,400 MHz): 7.98 (d, J = 3.3 Hz, LC/MS: calc'd 1H), 7.76 (d, J = 3.0 Hz,1H), 7.41 (dd, J = 8.7, 6.1 Hz, 1H), 507 (MH⁺), exp 7.24 (dd, J = 8.8,2.8 Hz, 1H), 7.04 (td, J = 8.4, 2.8 Hz, 1H), 507 (MH⁺) 6.17 (s, 1H),4.52 (d, J = 17.8 Hz, 1H), 4.04-4.16 (m, 4H), 3.86 (m, 2H), 3.62 (s,3H), 2.86 (m, 1H), 2.77 (m, 1H), 2.49 (m, 2H), 1.73 (m, 2 H). 8 ¹H NMR(METHANOL-d4, 400 MHz): 7.98 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.76 (d,J = 3.0 Hz, 1H), 7.41 (dd, J = 8.7, 6.1 Hz, 1H), 549 (MH⁺), exp 7.24(dd, J = 8.8, 2.5 Hz, 1H), 7.04 (td, J = 8.4, 2.5 Hz, 1H), 549 (MH⁺)6.18 (s, 1H), 5.86 (m, 1H), 4.53 (d, J = 17.8 Hz, 1H), 4.08 (d, J = 17.8Hz, 1H), 4.04 (m, 2H), 3.86 (dd, J = 18.3, 11.0 Hz, 2H), 3.63 (s, 3H),2.96 (m, 1H), 2.83 (m, 1H), 2.07 (s, 3H), 2.05 (m, 4H). 9 ¹H NMR(METHANOL-d4, 400 MHz): 7.97 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.75 (d,J = 3.3 Hz, 1H), 7.41 (dd, J = 8.7, 6.1 Hz, 1H), 507 (MH⁺), exp 7.23(dd, J = 8.7, 2.6 Hz, 1H), 7.04 (td, J = 8.4, 2.8 Hz, 1H), 507 (MH⁺)6.17 (s, 1H), 4.73 (m, 1H), 4.49 (d, J = 17.8 Hz, 1H), 3.97-4.14 (m,3H), 3.82 (dd, J = 17.8, 11.0 Hz, 2H), 3.63 (s, 3H), 2.91 (m, 1H), 2.79(m, 1H), 1.84-2.09 (m, 4 H). 10 ¹H NMR (METHANOL-d4, 400 MHz): 7.87 (d,J = 3.2 Hz, LC/MS: calc'd 1H), 7.75 (d, J = 3.1 Hz, 1H), 7.42 (m, 1H),7.24 (m, 1H), 7.06 537 (MH⁺), exp (m, 1H), 6.18 (s, 1H), 4.54 (d, J =14.6, 1H), 4.12 (d, J = 13.0, 537 (MH⁺) 1H), 4.04 (m, 1H), 3.88 (s, 2H),3.70 (m, 2H), 3.63 (s, 3H), 2.84 (m, 2H), 2.14 (m, 2H), 1.98 (m, 2H). 11¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J = 3.0 Hz, LC/MS: calc'd 1H),7.77 (d, J = 3.3 Hz, 1H), 7.43 (dd, J = 8.8, 6.0 Hz, 1H), 570 (MH⁺), exp7.24 (dd, J = 8.8, 2.8 Hz, 1H), 7.05 (td, J = 8.4, 2.8 Hz, 1H), 570(MH⁺) 6.18 (s, 1H), 4.68 (d, J = 17.3 Hz, 1H), 4.16-4.22 (m, 3H), 3.95(m, 2H), 3.73 (m, 2H), 3.63 (s, 3H), 3.54 (m, 2H), 2.94 (s, 3H), 2.86(m, 2 H). 12 ¹H NMR (METHANOL-d4, 400 MHz): 8.18 (d, J = 3.3 Hz, LC/MS:calc'd 1H), 8.10 (d, J = 3.0 Hz, 1H), 7.56 (dd, J = 8.8, 6.0 Hz, 1H),506 (MH⁺), exp 7.34 (dd, J = 8.7, 2.6 Hz, 1H), 7.15 (td, J = 8.3, 2.6Hz, 1H), 506 (MH⁺) 6.28 (s, 1H), 4.56 (d, J = 16.1 Hz, 1H), 4.20 (m,3H), 4.10 (m, 2H), 3.72 (m, 1H), 3.68 (m, 1H), 3.67 (s, 3H), 3.54-3.61(m, 2H), 3.16 (m, 2H), 2.95 (s, 3 H). 13 ¹H NMR (METHANOL-d4, 400 MHz):7.96 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.77 (d, J = 3.3 Hz, 1H), 7.41(dd, J = 8.7, 6.1 Hz, 1H), 534 (MH⁺), exp 7.24 (dd, J = 8.8, 2.8 Hz,1H), 7.05 (td, J = 8.5, 2.6 Hz, 1H), 534 (MH⁺) 6.18 (s, 1H), 4.62 (d, J= 18.1 Hz, 1H), 4.09-4.21 (m, 3H), 3.91 (m, 2H), 3.63 (s, 3H), 3.02 (m,4H), 2.79 (m, 2H), 2.70 (m, 1H), 1.20 (d, J = 5.8 Hz, 6 H). 14 ¹H NMR(METHANOL-d4, 400 MHz): 8.09 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.97 (d,J = 3.0 Hz, 1H), 7.52 (dd, J = 8.8, 6.0 Hz, 2H), 556 (MH⁺), exp 7.31(dd, J = 8.5, 2.5 Hz, 1H), 7.11 (td, J = 8.3, 2.6 Hz, 1H), 556 (MH⁺)6.47 (m, 1H), 6.24 (s, 1H), 4.65 (d, J = 16.3 Hz, 1H), 4.30 (d, J = 16.3Hz, 1H), 4.23 (m, 2H), 4.15 (m, 2H), 3.72 (m, 4H), 3.66 (s, 3H), 3.64(m, 2H), 3.30 (m, 2H). 15 ¹H NMR (METHANOL-d4, 400 MHz): 8.02-8.09 (m,1H), LC/MS: calc'd 7.97 (d, J = 3.0 Hz, 1H), 7.57 (dd, J = 8.7, 5.9 Hz,1H), 7.31 534 (MH⁺), exp (dd, J = 8.7, 2.6 Hz, 1H), 7.13 (td, J = 8.4,2.5 Hz, 1H), 6.24 (s, 534 (MH⁺) 1H), 5.03 (dd, J = 16.9, 2.1 Hz, 1H),4.91 (m, 1H), 4.68 (d, J = 16.8 Hz, 1H), 4.19-4.37 (m, 4H), 4.03-4.14(m, 2H), 3.67 (s, 3H), 3.45-3.59 (m, 3H), 2.20 (d, J = 0.7 Hz, 3 H). 16¹H NMR (METHANOL-d4, 400 MHz): 8.07 (d, J = 3.3 Hz, LC/MS: calc'd 1H),7.97 (d, J = 3.3 Hz, 1H), 7.56 (dd, J = 8.7, 5.9 Hz, 1H), 585 (MH⁺), exp7.31 (dd, J = 8.7, 2.6 Hz, 1H), 7.13 (td, J = 8.4, 2.5 Hz, 1H), 585(MH⁺) 6.24 (s, 1H), 4.98 (d, J = 17.1 Hz, 1H), 4.59 (d, J = 15.1 Hz,1H), 4.31 (d, J = 12.8 Hz, 2H), 4.11 (d, J = 12.8 Hz, 2H), 3.84 (dd, J =13.4, 6.40 Hz, 2H), 3.62-3.75 (m, 5H), 3.50 (d, J = 1.8 Hz, 2H), 2.72(s, 3 H). 17 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.3 Hz, LC/MS:calc'd 1H), 7.79 (d, J = 3.3 Hz, 1H), 7.44 (dd, J = 8.8, 6.0 Hz, 1H),550 (MH⁺), exp 7.25 (dd, J = 8.7, 2.6 Hz, 1H), 7.06 (td, J = 8.4, 2.5Hz, 1H), 550 (MH⁺) 6.19 (s, 1H), 4.72 (d, J = 17.3 Hz, 1H), 4.11-4.32(m, 5H), 3.89- 4.01 (m, 2H), 3.75 (s, 3H), 3.53-3.71 (m, 5H), 2.72-2.89(m, 2 H). 18 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.3 Hz, LC/MS:calc'd 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 8.8, 6.0 Hz, 1H),535 (MH⁺), exp 7.24 (dd, J = 8.8, 2.51 Hz, 1H), 7.05 (td, J = 8.4, 2.8Hz, 1H), 535 (MH⁺) 6.18 (s, 1H), 4.67 (d, J = 17.6 Hz, 1H), 4.10-4.26(m, 3H), 3.98- 4.07 (m, 2H), 3.87-3.96 (m, 2H), 3.63 (s, 3H), 3.57 (m,2H), 2.75 (d, J = 19.3 Hz, 2 H). 19 ¹H NMR (METHANOL-d4, 400 MHz):7.92-8.03 (m, 1H), LC/MS: calc'd 7.76 (d, J = 3.0 Hz, 1H), 7.43 (dd, J =8.7, 6.1 Hz, 1H), 7.24 571 (MH⁺), exp (dd, J = 8.8, 2.5 Hz, 1H), 7.05(td, J = 8.4, 2.8 Hz, 1H), 6.18 (s, 571 (MH⁺) 1H), 4.58-4.72 (m, 1H),4.10-4.26 (m, 3H), 3.89-4.01 (m, 2H), 3.62 (s, 3H), 3.53-3.61 (m, 2H),3.39-3.48 (m, 2H), 2.92 (m, 1H), 2.80-2.89 (m, 1 H). 20 ¹H NMR(METHANOL-d4, 400 MHz): 7.97 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.76 (d,J = 3.0 Hz, 1H), 7.41 (dd, J = 8.8, 6.0 Hz, 1H), 606 (MH⁺), exp 7.23(dd, J = 8.8, 2.5 Hz, 1H), 7.04 (td, J = 8.4, 2.5 Hz, 1H), 606 (MH⁺)6.15-6.20 (m, 1H), 4.62 (d, J = 17.8 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H),4.11-4.20 (m, 3H), 3.87 (t, J = 10.9 Hz, 2H), 3.62 (s, 3H), 3.09-3.17(m, 2H), 2.98 (d, J = 11.5 Hz, 2H), 2.71-2.81 (m, 2H), 1.40 (s, 6H),1.35 (t, J = 7.1 Hz, 3 H). 21 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (dd, J= 3.0, 1.8 LC/MS: calc'd Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.43 (dd, J= 8.8, 6.0 Hz, 550 (MH⁺), exp 1H), 7.24 (dd, J = 8.7, 2.6 Hz, 1H),7.01-7.09 (m, 1H), 6.18 (s, 550 (MH⁺) 1H), 4.69 (d, J = 17.6 Hz, 1H),4.54 (d, J = 13.8 Hz, 1H), 4.18- 4.36 (m, 3H), 4.15 (dt, J = 11.3, 2.5Hz, 2H), 3.86-4.02 (m, 2H), 3.79 (d, J = 6.8 Hz, 2H), 3.63 (s, 3H), 3.44(t, J = 11.2 Hz, 1H), 2.78 (t, J = 16.6 Hz, 2 H). 22 ¹H NMR(METHANOL-d4, 400 MHz): 8.00 (m, 1H), 7.72 (m, LC/MS: calc'd 1H), 7.45(m, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.17 (s, 1H), 592 (MH⁺), exp 4.60(m, 1H), 3.75-4.16 (m, 6H), 3.45 (m, 1H), 3.62 (s, 3H), 592 (MH⁺) 3.06(m, 2H), 2.77 (m, 2H), 1.37 (s, 9 H). 23 ¹H NMR (METHANOL-d4, 400 MHz):7.97 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.54(dd, J = 8.7, 6.1 Hz, 1H), 555 (MH⁺), exp 7.27 (dd, J = 8.7, 2.6 Hz,1H), 7.15 (td, J = 8.4, 2.5 Hz, 1H), 555 (MH⁺) 6.19 (s, 1H), 4.10 (m,2H), 3.85 (m, 1H), 3.65 (s, 3H), 2.85 (m, 2H), 2.40 (m, 1H), 2.20 (m,1H), 1.79-2.04 (m, 4 H). 24 ¹H NMR (DMSO-d6, DMSO-d6): 12.05 (brs., 1H),10.04 (s, LC/MS: calc'd 1H), 8.00 (d, J = 3.3 Hz, 1H), 7.94 (d, J = 3.0Hz, 1H), 7.34- 549 (MH⁺), exp 7.48 (m, 2H), 7.16 (td, J = 8.5, 2.6 Hz,1H), 6.04 (s, 1H), 4.34 549 (MH⁺) (d, J = 18.1, 1H), 4.14 (d, J = 17.8Hz, 1H), 3.80 (m, 2H), 3.53 (s, 3H), 3.44 (dd, J = 10.8, 3.5 Hz, 2H),2.84 (m, 2H), 2.43 (m, 1H), 2.35 (m, 2H), 2.23 (m, 2H), 1.29 (m, 2 H).25 ¹H NMR (METHANOL-d4, 400 MHz): 7.96-8.02 (m, 1H), LC/MS: calc'd 7.75(d, J = 3.3 Hz, 1H), 7.41 (dd, J = 8.7, 6.1 Hz, 1H), 7.23 563 (MH⁺), exp(dd, J = 8.8, 2.5 Hz, 1H), 7.04 (td, J = 8.4, 2.8 Hz, 1H), 6.17 (s, 563(MH⁺) 1H), 4.47-4.59 (m, 1H), 4.14 (d, J = 17.8 Hz, 1H), 4.01 (ddd, J =11.2, 7.4, 2.0 Hz, 2H), 3.69 (s, 3H), 3.61 (s, 3H), 3.45-3.55 (m, 2H),2.84 (t, J = 8.5 Hz, 2H), 2.60-2.73 (m, 1H), 2.50- 2.59 (m, 2H), 2.37(dq, J = 14.3, 7.0 Hz, 2H), 1.38-1.51 (m, 2 H). 26 ¹H NMR (METHANOL-d4,400 MHz): 7.89-8.03 (m, 1H), LC/MS: calc'd 7.73-7.83 (m, 1H), 7.49 (dd,J = 8.8, 6.0 Hz, 1H), 7.24 (dd, J = 563 (MH⁺), exp 8.7, 2.6 Hz, 1H),7.07 (td, J = 8.4, 2.5 Hz, 1H), 6.11-6.24 (m, 563 (MH⁺) 1H), 4.72 (d, J= 17.6 Hz, 1H), 4.30-4.46 (m, 1H), 3.95-4.18 (m, 4H), 3.65 (dd, J =11.8, 4.3 Hz, 2H), 3.11-3.27 (m, 2H), 2.60-2.73 (m, 1H), 2.42-2.60 (m,4H), 1.52-1.70 (m, 2H), 1.03-1.26 (m, 3 H). 27 ¹H NMR (METHANOL-d4, 400MHz): 8.07 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.78 (d, J = 3.1 Hz, 1H),7.12-7.26 (m, 3H), 5.72 (s, 1H), 533 (MH⁺), exp 4.52 (d, J = 18.1 Hz,1H), 4.05 (d, J = 18.1 Hz, 1H), 3.99 (m, 533 (MH⁺) 2H), 3.72 (s, 3H),3.52 (m, 2H), 2.82 (m, 2H), 2.56 (m, 1H), 2.28-2.43 (m, 4H), 1.43 (m, 2H). 28 ¹H NMR (METHANOL-d4, 400 MHz): 7.99 (d, J = 3.0 Hz, LC/MS: calc'd1H), 7.74 (d, J = 3.0 Hz, 1H), 7.33-7.49 (m, 2H), 7.09 (td, J = 593&595(MH⁺), 8.4, 2.5 Hz, 1H), 6.11-6.19 (m, 1H), 4.56 (d, J = 17.8 Hz, 1H),exp 593&595 4.16 (d, J = 18.3 Hz, 1H), 3.96-4.08 (m, 2H), 3.65 (s, 3H),3.53 (MH⁺) (d, J = 11.5 Hz, 2H), 2.86 (m, 2H), 2.59-2.69 (m, 1H), 2.47(d, J = 7.0 Hz, 2H), 2.42 (m, 2H), 1.39-1.54 (m, 2 H). 29 ¹H NMR(METHANOL-d4, 400 MHz): 8.03 (d, J = 3.1 Hz, LC/MS: calc'd 1H), 7.79 (d,J = 2.9 Hz, 1H), 7.12-7.28 (m, 3H), 5.73 (s, 1H), 547 (MH⁺), exp 4.57(d, J = 19.4 Hz, 1H), 4.07-4.23 (m, 3H), 3.95-4.03 (m, 547 (MH⁺) 2H),3.52 (d, J = 11.9 Hz, 2H), 2.76-2.88 (m, 2H), 2.59-2.68 (m, 1H), 2.46(d, J = 7.1 Hz, 2H), 2.38 (m, 2H), 1.39-1.51 (m, 2H), 1.27 (t, J = 7.1Hz, 3 H). 30 ¹H NMR (METHANOL-d4, 400 MHz): 8.01 (d, J = 3.0 Hz, LC/MS:calc'd 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.40 (dd, J = 8.5, 6.3 Hz, 1H),579 (MH⁺), exp 7.23 (dd, J = 8.7, 2.6 Hz, 1H), 7.04 (td, J = 8.4, 2.0Hz, 1H), 579 (MH⁺) 6.17 (d, J = 3.0 Hz, 1H), 4.44-4.63 (m, 1H),4.32-4.40 (m, 1H), 4.07-4.23 (m, 1H), 3.94-4.05 (m, 2H), 3.76 (m, 3H),3.63 (s, 3H), 3.47-3.59 (m, 2H), 2.77-2.95 (m, 2H), 2.48-2.65 (m, 1H),2.11-2.27 (m, 2H), 1.83 (d, J = 2.5 Hz, 1H), 1.70 (m, 1 H). 31 ¹H NMR(METHANOL-d4, 400 MHz): 8.04 (d, J = 3.1 Hz, LC/MS: calc'd 0.5H), 8.03(d, J = 3.1 Hz, 0.5H), 7.95 (d, J = 3.0 Hz, 0.5H), 529 (MH⁺), exp 7.94(d, J = 3.0 Hz, 0.5H), 7.71 (s, 0.5H), 7.66 (s, 0.5H), 7.53 529 (MH⁺)(m, 1H), 7.29 (m, 1H), 7.12 (m, 1H), 6.18 (s, 1H), 5.08 (s, 0.5H), 4.95(s, 0.5H) 4.71 (m, 1H), 4.46 (m, 0.5H), 4.42 (m, 0.5H), 4.19-4.34 (m,3H), 4.12 (m, 1H), 3.90 (m, 1H), 3.57 (s, 1.5H), 3.55 (s, 1.5H), 3.53(m, 1H), 3.26 (m, 1H). 32 ¹H NMR (METHANOL-d4, 400 MHz): 8.00 (m, 1H),7.77 (m, LC/MS: calc'd 1H), 7.44 (m, 1H), 7.25 (m, 1H), 7.07 (m, 1H),6.17 (s, 0.5H), 543 (MH⁺), exp 6.15 (s, 0.5H), 4.11 (m, 3H), 3.85 (m,3H), 3.79 (m, 2H), 3.52 543 (MH⁺) (s, 1.5H), 3.50 (s, 1.5H), 3.20 (m,1H), 2.71 (m, 1H), 2.24 (s, 1.5H), 2.18 (s, 1.5H). 33 ¹H NMR(METHANOL-d4, 400 MHz): 8.00 (m, 1H), 7.77 (m, LC/MS: calc'd 1H), 7.44(m, 1H), 7.25 (m, 1H), 7.07 (m, 1H), 6.18 (s, 0.5H), 559 (MH⁺), exp 6.15(s, 0.5H), 4.11 (m, 3H), 3.90 (m, 2H), 3.61 (m, 7H), 3.28 559 (MH⁺) (m,1H), 3.05 (m, 2H), 2.60 (m, 1H). 34 ¹H NMR (METHANOL-d4, 400 MHz): 7.98(d, J = 3.0 Hz, LC/MS: calc'd 0.5H), 7.97 (d, J = 3.0 Hz, 0.5H), 7.76(d, J = 3.3 Hz, 1H), 7.42 520 (MH⁺), exp (dd, J = 8.7, 6.1 Hz, 0.5H),7.41 (dd, J = 8.7, 6.1 Hz, 0.5H), 520 (MH⁺) 7.24 (dd, J = 8.8, 2.8 Hz,1H), 7.04 (m, 1H), 6.19 (s, 0.5H), 6.18 (s, 0.5H), 4.71 (d, J = 17.6 Hz,0.5H), 4.64 (d, J = 17.6 Hz, 0.5H), 4.23 (d, J = 17.6 Hz, 0.5H), 4.21(d, J = 17.6 Hz, 0.5H), 4.08 (m, 2H), 3.85-4.0 (m, 3H), 3.63 (s, 3H),3.26 (m, 2H), 2.70- 3.00 (m, 2H), 2.49 (m, 1H). 35 ¹H NMR (METHANOL-d4,400 MHz): 7.99 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.76 (d, J = 3.3 Hz,1H), 7.40 (dd, J = 8.7, 6.1 Hz, 1H), 538 (MH⁺), exp 7.24 (dd, J = 8.8,2.6 Hz, 1H), 6.99-7.10 (m, 1H), 6.17 (s, 1H), 538 (MH⁺) 4.55 (d, J =17.8 Hz, 1H), 4.46 (m, 1H), 4.04-4.19 (m, 3H), 3.86 (m, 2H), 3.63 (s,3H), 2.80 (m, 1H), 2.74 (m, 1H), 2.52 (m, 2H), 1.59 (m, 2 H). 36 ¹H NMR(METHANOL-d4, 400 MHz): 7.99 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.76 (d,J = 3.3 Hz, 1H), 7.41 (dd, J = 8.7, 6.1 Hz, 1H), 584 (MH⁺), exp 7.23(dd, J = 8.8, 2.5 Hz, 1H), 7.04 (td, J = 8.4, 2.8 Hz, 1H), 584 (MH⁺)6.17 (s, 1H), 4.53 (d, J = 17.6 Hz, 1H), 4.14 (m, 2H), 4.08 (d, J = 17.6Hz, 1H), 3.72-3.96 (m, 3H), 3.63 (s, 3H), 3.02 (s, 3H), 2.82 (m, 1H),2.75 (m, 1H), 2.58 (m, 2H), 1.78 (m, 2 H). 37 ¹H NMR (METHANOL-d4, 400MHz): 7.96 (d, J = 3.0 Hz, LC/MS: calc'd 1H), 7.75 (d, J = 3.3 Hz, 1H),7.34-7.44 (m, 1H), 7.23 (dd, J = 463 (MH⁺), exp 8.8, 2.3 Hz, 1H),6.97-7.09 (m, 1H), 6.16 (s, 1H), 4.13-4.46 463 (MH⁺) (m, 4H), 3.79-3.93(m, 2H), 3.63 (s, 3H), 3.57 (m, 1H), 3.34- 3.39 (m, 1H), 2.91 (m, 1H),1.96 (d, J = 8.5 Hz, 1 H). 38 ¹H NMR (METHANOL-d4, 400 MHz): 8.01 (d, J= 3.0 Hz, LC/MS: calc'd 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.55 (dd, J =8.5, 6.0 Hz, 1H), (MH⁺) 463 exp 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 7.13(td, J = 8.3, 2.5 Hz, 1H), 6.21 (MH⁺) 463. (s, 1H), 4.89-4.83 (m, 1H),4.81-4.69 (m, 3H), 4.10 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H),3.94-3.78 (m, 2H), 3.68 (s, 3H), 3.55-3.43 (m, 1H), 2.36(d, J = 10.3 Hz,1 H). 39 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (s, 1H), 7.75 LC/MS: calc'd(s, 1H), 7.51 (m, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 6.19 (s, 1H), 493(MH⁺), exp 4.35~4.15 (m, 3H), 3.8~3.92 (m, 3H), 3.60 (s, 3H), 3.59 (1H,493 (MH⁺) m), 3.10 (m, 1H), 2.80 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H). 40¹H NMR (METHANOL-d4, 400 MHz): 8.00 (d, J = 3.0 Hz, LC/MS: calc'd 1H),7.90 (d, J = 3.3 Hz, 1H), 7.56 (dd, J = 8.5, 6.0 Hz, 1H), 509 (MH⁺), exp7.29 (dd, J = 8.5, 2.5 Hz, 1H), 7.12 (td, J = 8.3, 2.6 Hz, 1H), 509(MH⁺) 6.20 (s, 1H), 4.99 (m, 1H), 3.88 (m, 1H), 3.63 (s, 3H), 3.37 (s,2H), 2.74 (d, J = 7.8 Hz, 4 H). 41 ¹H NMR (METHANOL-d4, 400 MHz): 7.99(m, 1H), 7.76- LC/MS: calc'd 7.90 (m, 1H), 7.41-7.53 (m, 1H), 7.20-7.31(m, 1H), 7.01- 504 (MH⁺), exp 7.15 (m, 1H), 6.16 (s, 1H), 4.17-4.82 (m,3H), 3.74-4.11 (m, 504 (MH⁺) 3H), 3.37-3.72 (m, 5H), 1.85-2.52 (m, 5 H).42 ¹H NMR (METHANOL-d4, 400 MHz): 7.95-8.03 (m, 1H), LC/MS: calc'd 7.76(d, J = 3.3 Hz, 1H), 7.41 (dd, J = 8.8, 6.3 Hz, 1H), 7.24 565 (MH⁺), exp(dd, J = 8.8, 2.5 Hz, 1H), 7.05 (td, J = 8.4, 2.5 Hz, 1H), 6.17 (s, 565(MH⁺) 1H), 4.56 (d, J = 17.8 Hz, 1H), 3.96-4.13 (m, 2H), 3.64 (s, 3H),3.46-3.60 (m, 2H), 3.05-3.18 (m, 2H), 2.37-2.50 (m, 2H), 2.22 (d, J =7.0 Hz, 2H), 1.95-2.05 (m, 2H), 1.80-1.95 (m, 2 H). 43 ¹H NMR(METHANOL-d4, 400 MHz): 8.00 (d, J = 3.2 Hz, LC/MS: calc'd 1H), 7.77 (d,J = 3.2 Hz, 1H), 7.43 (dd, J = 8.8, 6.0 Hz, 1H), 517 (MH⁺), exp 7.25(dd, J = 8.8, 2.8 Hz, 1H), 7.05 (td, J = 8.4, 2.8 Hz, 1H), 517 (MH⁺)6.19 (s, 1H), 4.63 (d, J = 17.2 Hz, 1H), 4.15 (m, 3H), 3.89 (m, 2H),3.65 (s, 3H), 2.89 (m, 2H), 2.44 (td, J = 14.0, 5.0 Hz, 2H), 0.60 (m,2H). 44 ¹H NMR (METHANOL-d4, 400 MHz): 8.01 (d, J = 3.2 Hz, LC/MS:calc'd 1H), 7.90 (d, J = 3.2 Hz, 1H), 7.55 (dd, J = 8.8, 6 Hz, 1H), 7.31491 (MH⁺), exp (d, J = 8.8, 2.4 Hz, 1H), 7.12 (td, J = 8.3, 2.6 Hz, 1H),6.20 (s, 491 (MH⁺) 1H), 4.65 (d, J = 16.6 Hz, 1H), 4.43 (d, J = 16.6 Hz,1H), 4.19 (m, 2H), 4.08 (m, 1H), 3.64 (s, 3H), 2.67 (m, 2H), 2.53 (m,2H), 2.32 (m, 2H), 2.21 (m, 2 H). 45 ¹H NMR (METHANOL-d4, 400 MHz): 8.01(d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.78 (d, J = 3.3 Hz, 1H), 7.39-7.49(m, 2H), 7.23 (dd, J = 8.7, 2.6 515 (MH⁺), exp Hz, 1H), 7.06 (td, J =8.4, 2.8 Hz, 1H), 6.17 (s, 1H), 3.85-4.24 515 (MH⁺) (m, 5H), 3.58-3.85(m, 3H), 3.51 (s, 3H). 46 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, J =3.0 Hz, 1H), LC/MS: calc'd 7.81 (d, J = 3.0 Hz, 1H), 7.08-7.34 (m, 3H),5.72 (s, 1H), 4.54 549 (MH⁺), exp (d, J = 17.6 Hz, 1H), 4.17 (s, 2H),3.94-4.12 (m, 4H), 3.71 (s, 549 (MH⁺) 3H), 3.70 (2H, m), 2.76-2.93 (m,2H), 2.47 (m, 2H), 1.86(m, 2H). 47 ¹H NMR (METHANOL-d4, 400 MHz): 8.02(d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.81 (d, J = 3.0 Hz, 1H), 7.08-7.34(m, 3H), 5.72 (s, 1H), 4.54 549 (MH⁺), exp (d, J = 17.6 Hz, 1H), 4.17(s, 2H), 3.94-4.12 (m, 4H), 3.71 (s, 549 (MH⁺) 3H), 3.70 (2H, m),2.76-2.93 (m, 2H), 2.47 (m, 2H), 1.86(m, 2H). 48 ¹H NMR (METHANOL-d4,400 MHz): 7.97 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.76 (d, J = 3.3 Hz,1H), 7.43 (m, 1H), 7.23 (dd, J = 8.7, 2.6 Hz, 534 (MH⁺), exp 1H), 7.06(td, J = 8.4, 2.4 Hz, 0.5H), 7.05 (td, J = 8.4, 2.4 Hz, 534 (MH⁺) 0.5H),6.17 (s, 1H), 4.68 (m, 1H), 4.17 (m, 1H), 3.63-4.09 (m, 5H), 3.61 (s,3H), 3.30 (m, 0.5H), 3.20 (m, 1H), 3.08 (m, 0.5H), 2.63 (m, 1H), 2.03(s, 1.5H), 2.02 (s, 1.5H), 1.85 (m, 1H). 49 ¹H NMR (METHANOL-d4, 400MHz): 7.98 (d, J = 3.1 Hz, LC/MS: calc'd 0.5H), 7.97 (d, J = 3.1 Hz,0.5H), 7.77 (d, J = 3.1 Hz, 1H), 7.44 493 (MH⁺), exp (dd, J = 8.7, 6.1Hz, 0.5H), 7.43 (dd, J = 8.7, 6.1 Hz, 0.5H), 7.24 493 (MH⁺) (dd, J =8.8, 2.8 Hz, 1H), 7.06 (tt, J = 8.4, 2.8 Hz, 1H), 6.18 (s, 1H), 4.66 (m,1H), 4.51 (m, 1H), 4.20 (m, 1H), 3.71-3.98 (m, 3H), 3.61 (s, 1.5H), 3.60(s, 1.5H) 3.48-3.59 (m, 1H), 3.19 (m, 1H), 3.09 (m, 1H), 2.40 (m, 1H),2.12 (m, 1H). 50 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.1 Hz,LC/MS: calc'd 0.5H) 7.97 (d, J = 3.1 Hz, 0.5H), 7.79 (d, J = 3.3 Hz,1H), 7.48 609, 611 (MH⁺), (m, 1H), 7.43 (m, 1H), 7.08-7.22 (m, 1H), 6.18(s, 0.5H), 6.16 exp 609, 611 (s, 0.5H), 4.21-4.71 (m, 3H), 4.01-4.20 (m,4H), 3.82-3.99 (m, (MH⁺) 3H), 3.43-3.78 (m, 3H), 2.38-2.56 (m, 1H), 2.32(d, J = 11.5 Hz, 1H), 1.16 ppm (t, J = 7.1 Hz, 1.5H), 1.15 (t, J = 7.1Hz, 1.5H). 51 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, J = 3.3 Hz, 1H),LC/MS: calc'd 7.92 (d, J = 3.0 Hz, 1H), 7.55 (m, 1H), 7.30 (dd, J = 8.7,2.6 Hz, 495 (MH⁺), exp 1H), 7.12 (td, J = 8.3, 2.6 Hz, 0.5H), 7.11 (dt,J = 8.3, 2.6 495 (MH⁺) Hz, 0.5H), 6.21 (s, 0.5H), 6.20 (s, 0.5H), 5.75(m, 0.5H), 5.61 (m, 0.5H), 4.92 (m, 1H), 4.71 (m, 1H), 4.29-4.54 (m,2H), 4.18 (m, 3H), 3.89 (m, 1H), 3.65 (s, 1.5H), 3.64 (s, 1.5H),2.58-2.97 (m, 2H). 52 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J = 3.3Hz, 1H), LC/MS: calc'd 7.76 (d, J = 3.0 Hz, 1H), 7.45 (m, 1H), 7.42 (dd,J = 8.4, 2.6 Hz, 579, 581 (MH⁺), 1H), 7.12 (td, J = 8.4, 2.5 Hz, 1H),6.18 (s, 1H), 4.17 (m, 1H), exp 579, 581 4.06 (q, J = 7.0 Hz, 2H), 3.97(m, 2H), 3.90 (m, 2H), 3.69 (m, (MH⁺) 1H), 3.45(m, 2H), 3.24 (m, 0.5H),3.07 (m, 0.5H), 2.45 (m, 1H), 2.33 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H). 53¹H NMR (METHANOL-d4, 400 MHz): 7.97 (dd, J = 3.01, 1.76 MS: calc'd Hz, 1H) 7.76 (d, J = 3.01 Hz, 1 H) 7.35-7.46 (m, 2 H) 7.09 (d, (MH⁺) 594, expJ = 2.51 Hz, 1 H) 6.17 (s, 1 H) 4.70 (d, J = 17.57 Hz, 1 H) 4.54 (MH⁺)594 (dd, J = 13.55, 2.51 Hz, 1 H) 4.11-4.36 (m, 5 H) 3.84-4.01 (m, 2 H)3.73-3.84 (m, 2 H) 3.63 (s, 3 H) 3.40-3.52 (m, 1 H) 2.78 (t, J = 17.19Hz, 2 H). 54 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J = 3.26 Hz, 1 MS:calc'd H) 7.76 (d, J = 3.01 Hz, 1 H) 7.35-7.49 (m, 2 H) 7.09 (td, J =(MH⁺) 579, exp 8.41, 2.51 Hz, 1 H) 6.17 (s, 1 H) 4.68 (d, J = 17.57 Hz,1 H) (MH⁺) 579 4.11-4.25 (m, 3 H) 3.99 (d, J = 5.77 Hz, 2 H) 3.89-3.97(m, 2 H) 3.63 (s, 3 H) 3.57 (br. s., 2 H) 2.78 (br. s., 1 H) 2.73 (br.s., 1 H). 55 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, J = 3.26 Hz, 1LC/MS: calc'd H) 7.92 (d, J = 3.26 Hz, 1 H) 7.31-7.42 (m, 2 H) 7.25(ddd, J = 550 (MH⁺), exp 9.10, 7.09, 2.38 Hz, 1 H) 6.22-6.30 (m, 1 H)5.05 (d, J = 16.81 550 (MH⁺) Hz, 1 H) 4.71 (d, J = 17.07 Hz, 1 H)4.16-4.27 (m, 2 H) 3.85 (br. s., 2 H) 3.68-3.80 (m, 2 H) 3.60-3.68 (m, 3H) 2.56-2.80 (m, 5 H) 1.90 (d, J = 6.53 Hz, 2 H). 56 ¹H NMR(METHANOL-d4, 400 MHz): 8.02 (d, J = 3.26 Hz, 1 LC/MS: calc'd H) 7.92(d, J = 3.26 Hz, 1 H) 7.56 (dd, J = 8.78, 6.02 Hz, 1 H) 586 (MH⁺), exp7.30 (dd, J = 8.66, 2.64 Hz, 1 H) 7.12 (td, J = 8.34, 2.64 Hz, 1 586(MH⁺) H) 6.16-6.25 (m, 1 H) 5.03 (d, J = 16.81 Hz, 1 H) 4.73 (d, J =17.07 Hz, 1 H) 4.64 (dt, J = 11.98, 5.93 Hz, 1 H) 4.26-4.35 (m, 2 H)4.12-4.24 (m, 2 H) 3.79 (br. s., 2 H) 3.67 (s, 3 H) 2.58 (br. s., 2 H)2.20-2.38 (m, 2 H). 57 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, J = 3.26Hz, 1 LC/MS: calc'd H) 7.93 (d, J = 3.26 Hz, 1 H) 7.56 (dd, J = 8.78,6.02 Hz, 1 H) 550 (MH⁺), exp 7.30 (dd, J = 8.78, 2.51 Hz, 1 H) 7.13 (td,J = 8.41, 2.76 Hz, 1 550 (MH⁺) H) 6.21 (s, 1 H) 5.06 (d, J = 16.56 Hz, 1H) 4.89-4.94 (m, 1 H) 4.76 (d, J = 16.56 Hz, 1 H) 4.09-4.35 (m, 4 H)3.78 (br. s., 2 H) 3.67 (s, 3 H) 2.43 (br. s., 2 H) 2.10-2.28 (m, 2 H).58 ¹H NMR ((METHANOL-d4, 400 MHz): 8.01 (d, J = 3.01 Hz, 1 LC/MS: calc'dH) 7.88-7.94 (m, 1 H) 7.52-7.65 (m, 1 H) 7.46 (d, J = 2.76 594(MH⁺), expHz, 1 H) 7.17 (td, J = 8.34, 2.64 Hz, 1 H) 6.20 (s, 1 H) 5.08 (d, J =594 (MH⁺) 15.56 Hz, 1 H) 4.73 (dd, J = 16.06, 8.28 Hz, 1 H) 4.04-4.41(m, 4 H) 3.61-3.86 (m, 5 H) 3.15-3.29 (m, 1 H) 2.21-2.55 (m, 4 H) 2.14(t, J = 11.04 Hz, 2 H). 59 ¹H NMR (METHANOL-d4, 400 MHz): 7.97-8.06 (m,1 H) LC/MS: calc'd 7.92 (d, J = 3.26 Hz, 1 H) 7.32-7.45 (m, 2 H)7.15-7.28 (m, 1 550 (MH⁺), exp H) 6.26 (s, 1 H) 4.98-5.15 (m, 1 H)4.63-4.77 (m, 1 H) 4.30 550 (MH⁺) (br. s., 4 H) 3.59-3.83 (m, 5 H)3.15-3.29 (m, 1 H) 2.62-2.77 (m, 1 H) 2.38 (d, J = 6.78 Hz, 3 H) 2.14(br. s., 2 H). 60 ¹H NMR (METHANOL-d4, 400 MHz): 7.90-8.03 (m, 1 H)LC/MS: calc'd 7.76 (d, J = 3.26 Hz, 1 H) 7.41 (dd, J = 8.78, 6.02 Hz, 1H) 7.23 585 (MH⁺), exp (dd, J = 8.78, 2.51 Hz, 1 H) 7.04 (td, J = 8.41,2.76 Hz, 1 H) 585 (MH⁺) 6.17 (s, 1 H) 4.53 (d, J = 17.57 Hz, 1 H)4.01-4.23 (m, 3 H) 3.79-3.96 (m, 3 H) 3.63 (s, 3 H) 2.95-3.11 (m, 3 H)2.82 (br. s., 1 H) 2.75 (br. s., 1 H) 2.51-2.65 (m, 2 H) 1.78 (dd, J =13.55, 9.79 Hz, 2 H). 61 ¹H NMR (METHANOL-d4, 400 MHz): 7.99 (d, J =3.01 Hz, 1 LC/MS: calc'd H) 7.76 (d, J = 3.26 Hz, 1 H) 7.41 (dd, J =8.66, 6.15 Hz, 1 H) 549 (MH⁺), exp 7.24 (dd, J = 8.78, 2.76 Hz, 1 H)7.04 (td, J = 8.41, 2.76 Hz, 1 549 (MH⁺) H) 6.17 (s, 1 H) 4.55 (d, J =17.82 Hz, 1 H) 4.45 (t, J = 6.65 Hz, 1 H) 4.02-4.19 (m, 3 H) 3.76-3.92(m, 2 H) 3.63 (s, 3 H) 2.80 (br. s., 1 H) 2.73 (br. s., 1 H) 2.43-2.58(m, 2 H) 1.93-2.05 (m, 3 H) 1.51-1.66 (m, 2 H). 62 ¹H NMR (METHANOL-d4,400 MHz): 7.97 (d, J = 3.26 Hz, 1 LC/MS: calc'd H) 7.75 (d, J = 3.01 Hz,1 H) 7.40 (dd, J = 8.66, 6.15 Hz, 1 H) 550 (MH⁺), exp 7.23 (dd, J =8.78, 2.51 Hz, 1 H) 7.04 (d, J = 2.51 Hz, 1 H) 6.17 550 (MH⁺) (s, 1 H)4.53 (d, J = 17.82 Hz, 1 H) 4.18-4.32 (m, 1 H) 4.01- 4.18 (m, 3 H)3.77-3.91 (m, 2 H) 3.63 (s, 3 H) 2.70-2.79 (m, 2 H) 2.53 (dq, J = 14.40,7.08 Hz, 2 H) 1.59 (dd, J = 14.43, 9.91 Hz, 2 H). 63 ¹H NMR(METHANOL-d4, 400 MHz): 7.99 (d, J = 3.01 Hz, 1 LC/MS: calc'd H) 7.78(d, J = 2.76 Hz, 1 H) 7.39-7.47 (m, 1 H) 7.25 (dd, J = 586 (MH⁺), exp8.78, 2.51 Hz, 1 H) 7.05 (td, J = 8.34, 2.64 Hz, 1 H) 6.18 (s, 1 586(MH⁺) H) 4.58 (d, J = 17.82 Hz, 1 H) 4.16 (d, J = 10.04 Hz, 3 H) 3.77-3.98 (m, 3 H) 3.63 (s, 3 H) 2.83 (br. s., 2 H) 2.55 (br. s., 2 H) 1.95(br. s., 2 H). 64 ¹H NMR (METHANOL-d4, 400 MHz): 7.92-8.03 (m, 1 H)LC/MS: calc'd 7.71-7.84 (m, 1 H) 7.36-7.52 (m, 2 H) 7.11 (td, J = 8.41,2.51 579 (MH⁺), exp Hz, 1 H) 6.16 (s, 1 H) 4.32 (d, J = 16.81 Hz, 1 H)4.12 (d, J = 579 (MH⁺) 17.32 Hz, 1 H) 3.84-4.04 (m, 3 H) 3.70 (d, J =10.79 Hz, 1 H) 3.62 (s, 3 H) 3.44 (d, J = 9.29 Hz, 1 H) 3.27 (br. s., 1H) 2.84- 2.98 (m, 1 H) 2.64-2.81 (m, 2 H) 2.56 (td, J = 12.05, 7.28 Hz,1 H) 1.70 (dd, J = 12.92, 5.14 Hz, 1 H). 65 ¹H NMR (METHANOL-d4, 400MHz): 8.02 (d, J = 3.01 Hz, 1 LC/MS: calc'd H) 7.86-7.94 (m, 1 H)7.30-7.47 (m, 2 H) 7.25 (ddd, J = 9.16, 564 (MH⁺), exp 7.40, 2.01 Hz, 1H) 6.28 (s, 1 H) 5.04 (d, J = 17.07 Hz, 1 H) 564 (MH⁺) 4.71 (d, J =16.81 Hz, 1 H) 4.04-4.28 (m, 4 H) 3.86 (br. s., 2 H) 3.63-3.78 (m, 2 H)2.69 (d, J = 4.77 Hz, 5 H) 1.90 (d, J = 6.53 Hz, 2H) 1.14 (t, J = 7.15Hz, 3 H). 66 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.01 Hz, 1LC/MS: calc'd H) 7.77 (d, J = 3.01 Hz, 1 H) 7.21-7.34 (m, 2 H) 7.15 (td,J = 564 (MH⁺), exp 8.47, 1.88 Hz, 1 H) 6.24 (s, 1 H) 4.54 (d, J = 17.57Hz, 1 H) 564 (MH⁺) 4.07 (dd, J = 7.15, 0.88 Hz, 5 H) 3.84-3.96 (m, 2 H)3.07-3.21 (m, 1 H) 2.65-2.85 (m, 2 H) 2.23 (d, J = 7.03 Hz, 2 H) 1.70-1.94 (m, 4 H) 1.16 (t, J = 7.15 Hz, 3 H). 67 ¹H NMR (METHANOL-d4, 400MHz): 7.88-8.04 (m, 1 H) LC/MS: calc'd 7.66-7.81 (m, 1 H) 7.35-7.48 (m,2 H) 7.10 (td, J = 8.41, 2.51 608 (MH⁺), exp Hz, 1 H) 6.11-6.22 (m, 1 H)4.58 (d, J = 17.57 Hz, 1 H) 4.01- 608 (MH⁺) 4.27 (m, 5 H) 3.92 (t, J =11.17 Hz, 2 H) 3.15 (tt, J = 12.30, 6.02 Hz, 1 H) 2.76-2.94 (m, 2 H)2.17-2.31 (m, 2 H) 1.73- 1.99 (m, 4 H) 1.09-1.24 (m, 3 H). 68 ¹H NMR(METHANOL-d4, 400 MHz): 7.92-8.02 (m, 1 H) LC/MS: calc'd 7.77 (d, J =3.26 Hz, 1 H) 7.29-7.39 (m, 1 H) 7.24 (d, J = 7.78 608 (MH⁺), exp Hz, 1H) 7.13 (td, J = 8.28, 1.25 Hz, 1 H) 6.25 (s, 1 H) 4.60 (d, J = 608(MH⁺) 17.07 Hz, 1 H) 4.10-4.27 (m, 3 H) 4.01-4.10 (m, 2 H) 3.85- 3.98(m, 2 H) 3.15 (tt, J = 12.23, 6.21 Hz, 1 H) 2.74-2.98 (m, 2 H) 2.25 (d,J = 7.28 Hz, 2 H) 1.77-2.00 (m, 4 H) 1.15 (t, J = 7.15 Hz, 3 H). 69 ¹HNMR (METHANOL-d4, 400 MHz): 7.93-8.01 (m, 1 H) LC/MS: calc'd 7.77 (d, J= 3.01 Hz, 1 H) 7.13-7.28 (m, 2 H) 6.18 (s, 1 H) 4.54 582 (MH⁺), exp (d,J = 17.82 Hz, 1 H) 4.01-4.19 (m, 5 H) 3.91 (t, J = 11.54 582 (MH⁺) Hz, 2H) 3.04-3.20 (m, 1 H) 2.69-2.88 (m, 2 H) 2.23 (d, J = 7.03 Hz, 2 H)1.73-1.96 (m, 4 H) 1.17 (t, J = 7.03 Hz, 3 H). 70 ¹H NMR (METHANOL-d4,400 MHz): 7.98-8.07 (m, 1 H) LC/MS: calc'd 7.92 (d, J = 3.01 Hz, 1 H)7.54-7.65 (m, 1 H) 7.48 (dd, J = 606 (MH⁺), exp 8.41, 2.64 Hz, 1 H) 7.18(td, J = 8.34, 2.64 Hz, 1 H) 6.22 (s, 1 606 (MH⁺) H) 5.00-5.17 (m, 2 H)4.78 (d, J = 16.81 Hz, 1 H) 4.26-4.38 (m, 2 H) 4.03-4.24 (m, 4 H) 3.81(br. s., 2 H) 2.41 (br. s., 2 H) 2.18-2.32 (m, 2 H) 1.93-2.09 (m, 3 H)1.16 (t, J = 7.03 Hz, 3 H). 71 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, J= 3.01 Hz, 1 LC/MS: calc'd H) 7.93 (d, J = 3.01 Hz, 1 H) 7.57 (dd, J =8.78, 6.02 Hz, 1 H) 606 (MH⁺), exp 7.48 (dd, J = 8.41, 2.64 Hz, 1 H)7.18 (td, J = 8.34, 2.64 Hz, 1 606 (MH⁺) H) 6.22 (s, 1 H) 5.03 (d, J =16.81 Hz, 1 H) 4.73 (d, J = 16.56 Hz, 1 H) 4.51 (t, J = 7.03 Hz, 1 H)4.25-4.37 (m, 2 H) 4.04- 4.22 (m, 4 H) 3.75 (d, J = 4.27 Hz, 2 H)2.73-2.88 (m, 2 H) 2.03-2.16 (m, 2 H) 1.95-2.03 (m, 3 H) 1.16 (t, J =7.15 Hz, 3 H). 72 ¹H NMR (DMSO-d6, 400 MHz): 12.04 (br. s., 1 H) 9.98(s, 1 H) LC/MS: calc'd 8.01-8.09 (m, 1 H) 7.95 (d, J = 3.01 Hz, 1 H)7.44 (dd, J = 546 (MH⁺), exp 7.53, 1.76 Hz, 1 H) 7.38 (dd, J = 7.53,2.01 Hz, 1 H) 7.21-7.32 546 (MH⁺) (m, 2 H) 6.09 (s, 1 H) 4.33 (d, J =17.82 Hz, 1 H) 3.85-4.09 (m, 5 H) 3.71-3.83 (m, 2 H) 2.94 (dt, J =12.36, 6.24 Hz, 1 H) 2.75 (br. s., 1 H) 2.64 (br. s., 1 H) 2.09 (d, J =7.03 Hz, 2 H) 1.73 (td, J = 12.05, 5.02 Hz, 2 H) 1.60 (d, J = 13.05 Hz,2 H) 1.08 (t, J = 7.03 Hz, 3 H). 73 ¹H NMR (METHANOL-d4, 400 MHz): 7.98(d, J = 3.01 Hz, 1 LC/MS: calc'd H) 7.77 (d, J = 3.01 Hz, 1 H) 7.14-7.29(m, 2 H) 6.17 (s, 1 H) 568 (MH⁺), exp 4.53 (d, J = 17.32 Hz, 1 H)4.01-4.21 (m, 3 H) 3.90 (t, J = 568 (MH⁺) 11.67 Hz, 2 H) 3.63 (s, 3 H)3.08-3.22 (m, 1 H) 2.64-2.84 (m, 2 H) 2.24 (d, J = 6.78 Hz, 2 H)1.70-1.98 (m, 4 H). 74 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.01Hz, 1 LC/MS: calc'd H) 7.76 (d, J = 3.01 Hz, 1 H) 7.33 (td, J = 7.97,5.40 Hz, 1 H) 594 (MH⁺), exp 7.21 (d, J = 7.78 Hz, 1 H) 7.11 (td, J =8.28, 1.51 Hz, 1 H) 6.23 594 (MH⁺) (s, 1 H) 4.54 (d, J = 18.07 Hz, 1 H)4.01-4.20 (m, 3 H) 3.90 (t, J = 11.92 Hz, 2 H) 3.62 (s, 3 H) 3.13 (dd, J= 12.92, 5.90 Hz, 1 H) 2.65-2.85 (m, 2 H) 2.24 (d, J = 7.03 Hz, 2 H)1.86 (d, J = 8.53 Hz, 4 H). 75 ¹H NMR (METHANOL-d4, 400 MHz): 8.00 (d, J= 3.01 Hz, 1 LC/MS: calc'd H) 7.80 (d, J = 3.01 Hz, 1 H) 7.03-7.26 (m, 3H) 6.07 (s, 1 H) 547 (MH⁺), exp 4.51 (br. s., 1 H) 4.04-4.24 (m, 5 H)3.94 (d, J = 11.80 Hz, 2 H) 547 (MH⁺) 3.05-3.19 (m, 1 H) 2.82 (br. s., 2H) 2.24 (d, J = 7.03 Hz, 2 H) 1.84 (br. s., 4 H) 1.21 (t, J = 7.15 Hz, 3H). 76 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J = 3.26 Hz, 1 LC/MS:calc'd H) 7.76 (d, J = 3.01 Hz, 1 H) 7.61 (dd, J = 8.03, 1.25 Hz, 1 H)576 (MH⁺), exp 7.35-7.43 (m, 1 H) 7.31 (td, J = 7.47, 1.13 Hz, 1 H) 7.15(td, J = 576 (MH⁺) 7.65, 1.76 Hz, 1 H) 6.19 (s, 1 H) 4.55 (d, J = 18.07Hz, 1 H) 4.02-4.25 (m, 3 H) 3.84-3.96 (m, 2 H) 3.63 (s, 3 H) 3.08- 3.19(m, 1 H) 2.66-2.87 (m, 2 H) 2.24 (d, J = 7.03 Hz, 2 H) 1.73-1.99 (m, 4H). 77 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, J = 3.26 Hz, 1 LC/MS:calc'd H) 7.75 (d, J = 3.26 Hz, 1 H) 7.61 (dd, J = 8.03, 1.25 Hz, 1 H)590 (MH⁺), exp 7.35-7.45 (m, 1 H) 7.27-7.34 (m, 1 H) 7.16 (td, J = 7.65,1.76 590 (MH⁺) Hz, 1 H) 6.16-6.22 (m, 1 H) 4.54 (d, J = 17.57 Hz, 1 H)3.99- 4.21 (m, 5 H) 3.90 (t, J = 12.17 Hz, 2 H) 3.13 (dd, J = 12.05,6.02 Hz, 1 H) 2.62-2.84 (m, 2 H) 2.22 (d, J = 7.03 Hz, 2 H) 1.74-1.95(m, 4 H) 1.16 (t, J = 7.15 Hz, 3 H) 1H NMR (METHANOL-d4, 400 MHz): 7.98(d, J = 3.26 Hz, 1 H) 7.75 (d, J = 3.26 Hz, 1 H) 7.61 (dd, J = 8.03,1.25 Hz, 1 H) 7.35- 7.45 (m, 1 H) 7.27-7.34 (m, 1 H) 7.16 (td, J = 7.65,1.76 Hz, 1 H) 6.16-6.22 (m, 1 H) 4.54 (d, J = 17.57 Hz, 1 H) 3.99-4.21(m, 5H) 3.90 (t, J = 12.17 Hz, 2 H) 3.13 (dd, J = 12.05, 6.02 Hz, 1 H)2.62-2.84 (m, 2 H) 2.22 (d, J = 7.03 Hz, 2 H) 1.74- 1.95 (m, 4 H) 1.16(t, J = 7.15 Hz, 3 H). 78 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J =3.26 Hz, 1 LC/MS: calc'd H) 7.75 (d, J = 3.26 Hz, 1 H) 6.95-7.12 (m, 2H) 5.93 (s, 1 H) 561 (MH⁺), exp 4.57 (d, J = 17.57 Hz, 1 H) 4.03-4.22(m, 5 H) 3.91 (t, J = 561 (MH⁺) 12.17 Hz, 2 H) 3.07-3.21 (m, 1 H)2.68-2.88 (m, 2 H) 2.23 (d, J = 7.03 Hz, 2 H) 1.72-1.98 (m, 4 H) 1.19(t, J = 7.15 Hz, 3 H). 79 ¹H NMR (METHANOL-d4, 400 MHz4): 8.00 (d, J =3.01 Hz, 1 LC/MS: calc'd H) 7.83 (d, J = 3.26 Hz, 1 H) 7.47 (dd, J =8.66, 6.15 Hz, 1 H) 607 (MH⁺), exp 7.22-7.31 (m, 1 H) 7.07 (td, J =8.41, 2.76 Hz, 1 H) 6.20 (s, 1 607 (MH⁺) H) 4.77 (d, J = 16.81 Hz, 1 H)4.65 (br. s., 1 H) 4.33 (d, J = 17.57 Hz, 1 H) 4.18 (d, J = 11.80 Hz, 2H) 4.00 (d, J = 17.07 Hz, 2 H) 3.84 (br. s., 2 H) 3.64 (s, 3 H) 3.48 (d,J = 18.82 Hz, 1 H) 3.02 (br. s., 2 H) 1.36-1.58 (m, 6 H). 80 ¹H NMR(METHANOL-d4, 400 MHz): 7.91-8.04 (m, 1 H) LC/MS: calc'd 7.76 (d, J =3.01 Hz, 1 H) 7.17-7.31 (m, 2 H) 6.19 (s, 1 H) 4.55 626 (MH⁺), exp (d, J= 17.82 Hz, 1 H) 3.99-4.22 (m, 5 H) 3.91 (t, J = 11.67 626 (MH⁺) Hz, 2H) 3.13 (td, J = 11.92, 6.02 Hz, 1 H) 2.67-2.87 (m, 2 H) 2.23 (d, J =7.03 Hz, 2 H) 1.71-1.96 (m, 4 H) 1.17 (t, J = 7.15 Hz, 3 H). 81 ¹H NMR(METHANOL-d4, 400 MHz): 7.95-8.02 (m, 1 H) LC/MS: calc'd 7.80-7.88 (m, 1H) 7.50-7.60 (m, 1 H) 7.21-7.30 (m, 1 H) 521 (MH⁺), exp 7.01-7.12 (m, 1H) 6.13-6.22 (m, 1 H) 4.67-4.79 (m, 1 H) 521 (MH⁺) 4.36-4.49 (m, 1 H)4.07-4.22 (m, 2 H) 3.94-4.04 (m, 1 H) 3.70-3.85 (m, 2 H) 3.62 (s, 3 H)2.26-2.50 (m, 3 H) 2.14- 2.26 (m, 1 H). 82 ¹H NMR (METHANOL-d4, 400MHz): 7.98 (d, J = 3.14 Hz, 1 LC/MS: calc'd H) 7.84 (s, 1 H) 7.49-7.57(m, 1 H) 7.21-7.30 (m, 1 H) 7.04- 521 (MH⁺), exp 7.15 (m, 1 H) 6.19 (s,1 H) 4.80-4.89 (m, 1 H) 4.28-4.39 (m, 1 521 (MH⁺) H) 4.08-4.20 (m, 2 H)3.91-4.02 (m, 1 H) 3.80-3.90 (m, 1 H) 3.70-3.79 (m, 1 H) 3.62 (s, 3 H)2.31-2.50 (m, 3 H) 2.15- 2.27 (m, 1 H). 83 ¹H NMR (METHANOL-d4, 400MHz): 7.96-8.02 (m, 1 H) LC/MS: calc'd 7.78-7.86 (m, 1 H) 7.30-7.44 (m,2 H) 7.16-7.23 (m, 1 H) 535 (MH⁺), exp 6.25 (s, 1 H) 4.17-4.46 (m, 2 H)4.00-4.16 (m, 4 H) 3.88- 535(MH⁺) 3.96 (m, 1 H) 3.66-3.81 (m, 2 H)2.27-2.48 (m, 3 H) 2.13- 2.22 (m, 1H) 1.13 (td, J = 7.12, 1.94 Hz, 3 H).84 ¹H NMR (METHANOL-d4, 400 MHz): 7.97 (d, J = 3.14 Hz, 1 LC/MS: calc'dH) 7.79 (m, 1 H) 7.22 (m, 1 H) 7.00-7.12 (m, 1 H) 5.92 (s, 1 H)519(MH⁺), exp 4.75-4.86 (m, 1 H) 4.09 (m, 3 H) 3.92 (m, 2 H) 3.68-3.76(m, 1 519(MH⁺) H) 3.62 (s, 3 H) 2.54 (d, J = 2.26 Hz, 3 H) 2.35 (m, 3 H)2.04- 2.16 (m, 1 H). 85 ¹H NMR (METHANOL-d4, 400 MHz): 7.96 (d, J = 3.14Hz, 1 LC/MS: calc'd H) 7.72-7.84 (m, 1 H) 7.13-7.27 (m, 1 H) 7.05 (d, J= 9.29 519 (MH⁺), exp Hz, 1 H) 5.93 (s, 1 H) 4.65-4.78 (m, 1 H)4.15-4.26 (m, 1 H) 519(MH⁺) 4.01-4.14 (m, 3 H) 3.86-3.97 (m, 1 H)3.66-3.75 (m, 1 H) 3.63 (s, 3 H) 2.54 (d, J = 2.13 Hz, 3 H) 2.25-2.44(m, 3 H) 2.09- 2.22 (m, 1 H). 86 ¹H NMR (400 MHz, METHANOL-d4) 8.06-7.93(m, 1H), 7.79- LC/MS: calc'd 7.72 (m, 1H), 7.47-7.37 (m, 1H), 7.32-7.18(m, 1H), 7.13- 569 (MH⁺), exp 6.98 (m, 1H), 6.22-6.12 (m, 1H), 4.30-4.20(m, 2H), 3.62 (s, 569(MH⁺) 2H), 3.53-3.44 (m, 1H), 3.31-3.24 (m, 1H),2.88-2.65 (m, 2H), 2.50-2.21 (m, 4H), 2.05-1.93 (m, 1H), 1.84-1.58 (m,3H). 87 ¹H NMR (400 MHz, METHANOL-d4) 8.04-7.88 (m, 1H), 7.83- LC/MS:calc'd 7.69 (m, 1H), 7.29-7.20 (m, 1H), 7.11-7.00 (m, 1H), 6.18 (s, 569(MH⁺), exp 1H), 4.59-4.46 (m, 1H), 4.03-3.92 (m, 1H), 3.61 (s, 3H), 3.38569(MH⁺) (br. s., 2H), 2.85-2.60 (m, 2H), 2.35 (s, 4H), 2.11-2.01 (m,1H), 1.90-1.62 (m, 3H). 88 ¹H NMR (400 MHz, METHANOL-d4) 7.97 (d, J =3.0 Hz, 1H), LC/MS: calc'd 7.76 (d, J = 3.0 Hz, 1H), 7.39-7.21 (m, 2H),7.19-7.10 (m, 569 (MH⁺), exp 1H), 6.23 (s, 1H), 4.26 (s, 2H), 3.61 (s,3H), 3.50 (br. s., 1H), 569(MH⁺) 2.91-2.61 (m, 2H), 2.51-2.19 (m, 4H),1.98 (d, J = 12.0 Hz, 1H), 1.87-1.60 (m, 3H). 89 ¹H NMR (400 MHz,METHANOL-d4) 8.02-7.90 (m, 1H), 7.79- LC/MS: calc'd 7.71 (m, 1H),7.37-7.21 (m, 2H), 7.19-7.10 (m, 1H), 6.23 (s, 569 (MH⁺), exp 1H),4.56-4.44 (m, 1H), 4.06-3.89 (m, 2H), 3.61 (s, 3H), 3.39 569(MH⁺) (br.s., 1H), 2.86-2.61 (m, 2H), 2.50-2.19 (m, 4H), 2.04 (d, J = 14.1 Hz,1H), 1.90-1.63 (m, 3H). 90 ¹H NMR (400 MHz, METHANOL-d4) 8.04-7.94 (m,1H), 7.78- LC/MS: calc'd 7.70 (m, 1H), 7.45-7.36 (m, 2H), 7.30-7.19 (m,2H), 6.20 (s, 551 (MH⁺), exp 1H), 4.24 (s, 2H), 3.60 (s, 3H), 3.53-3.43(m, 1H), 3.30-3.25 551(MH⁺) (m, 1H), 2.86-2.66 (m, 1H), 2.50-2.22 (m,4H), 2.03-1.92 (m, 1H), 1.86-1.61 (m, 3H). 91 ¹H NMR (400 MHz,METHANOL-d4) 7.96 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.74 (d, J = 3.3Hz, 1H), 7.48-7.33 (m, 2H), 7.25 (ddd, J = 1.6, 551 (MH⁺), exp 7.3, 9.1Hz, 2H), 6.22 (s, 1H), 4.46 (d, J = 1.8 Hz, 1H), 3.96 (d, 551(MH⁺) J =17.8 Hz, 1H), 3.60 (s, 3H), 3.42-3.38 (m, 1H), 3.37 (br. s., 2H),2.82-2.63 (m, 1H), 2.48-2.21 (m, 4H), 2.09-1.98 (m, 1H), 1.89-1.59 (m,3H). 92 ¹H NMR (400 MHz, METHANOL-d4) 8.01-7.90 (m, 1H), 7.78- LC/MS:calc'd 7.70 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45-7.37 (m, 1H), 609(MH⁺), exp 7.32 (s, 1H), 7.21-7.07 (m, 1H), 6.19 (s, 1H), 4.25 (s, 2H),4.04 609 (MH⁺) (q, J = 7.0 Hz, 2H), 3.55-3.47 (m, 1H), 3.30 (br. s.,1H), 2.71 (d, J = 5.0 Hz, 1H), 2.48-2.22 (m, 4H), 1.96 (br. s., 1H),1.86- 1.61 (m, 3H), 1.15 (t, J = 7.0 Hz, 3H). 93 ¹H NMR (400 MHz,METHANOL-d4) 7.96 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.73 (d, J = 3.0Hz, 1H), 7.60 (dd, J = 1.1, 7.9 Hz, 1H), 7.41 609 (MH⁺), exp (dd, J =1.8, 7.8 Hz, 1H), 7.32 (dt, J = 1.0, 7.5 Hz, 1H), 7.15 (dt, 609 (MH⁺) J= 1.8, 7.7 Hz, 1H), 6.20 (s, 1H), 4.49 (dd, J = 1.6, 17.7 Hz, 1H),4.11-3.90 (m, 3H), 3.39 (d, J = 8.3 Hz, 2H), 2.71 (s, 1H), 2.48-2.17 (m,4H), 2.04 (d, J = 13.6 Hz, 1H), 1.89-1.73 (m, 2H), 1.66 (t, J = 12.7 Hz,1H), 1.15 (t, J = 7.2 Hz, 3H). 94 ¹H NMR (400 MHz, METHANOL-d4)8.02-7.93 (m, 1H), 7.79- LC/MS: calc'd 7.69 (m, 1H), 7.41-7.28 (m, 1H),7.27-7.18 (m, 1H), 7.15- 613 (MH⁺), exp 7.03 (m, 1H), 6.22 (s, 1H), 4.25(s, 2H), 3.60 (s, 3H), 3.51-3.42 613 (MH⁺) (m, 1H), 3.31-3.22 (m, 1H),2.85-2.66 (m, 1H), 2.49-2.18 (m, 4H), 2.05-1.91 (m, 1H), 1.85-1.61 (m,3H). 95 ¹H NMR (400 MHz, METHANOL-d4) 8.02-7.90 (m, 1H), 7.81- LC/MS:calc'd 7.64 (m, 1H), 7.39-7.27 (m, 1H), 7.26-7.18 (m, 1H), 7.15- 613(MH⁺), exp 7.04 (m, 1H), 6.28-6.16 (m, 1H), 4.57-4.41 (m, 1H), 4.04- 613(MH⁺) 3.90 (m, 1H), 3.60 (s, 3H), 3.44-3.34 (m, 2H), 2.79-2.63 (m, 1H),2.28 (s, 4H), 2.08-1.96 (m, 1H), 1.87-1.58 (m, 3H). 96 ¹H NMR (400 MHz,METHANOL-d4) 8.07-7.98 (m, 1H), 7.83- LC/MS: calc'd 7.74 (m, 1H),7.52-7.37 (m, 1H), 7.26-7.13 (m, 2H), 5.74 (s, 569 (MH⁺), exp 1H),4.33-4.06 (m, 2H), 3.70 (s, 3H), 3.46-3.37 (m, 1H), 3.29- 569 (MH⁺) 3.20(m, 1H), 2.82-2.62 (m, 1H), 2.46-2.15 (m, 4H), 2.02- 1.89 (m, 1H),1.85-1.57 (m, 3H). 97 ¹H NMR (400 MHz, METHANOL-d4) 8.13-7.94 (m, 1H),7.85- LC/MS: calc'd 7.74 (m, 1H), 7.48-7.35 (m, 1H), 7.30-7.08 (m, 2H),5.79- 569 (MH⁺), exp 5.67 (m, 1H), 4.57-4.41 (m, 1H), 3.99-3.84 (m, 1H),3.70 (s, 569 (MH⁺) 3H), 3.39-3.34 (m, 1H), 3.32-3.26 (m, 1H), 2.80-2.60(m, 1H), 2.48-2.16 (m, 4H), 2.07-1.94 (m, 1H), 1.88-1.54 (m, 3H). 98 ¹HNMR (400 MHz, METHANOL-d4) 7.98 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.75(d, J = 3.3 Hz, 1H), 7.36-7.21 (m, 2H), 7.19-7.10 (m, 583 (MH⁺), exp1H), 6.27-6.16 (m, 1H), 4.24 (d, J = 4.3 Hz, 2H), 4.12-3.99 583 (MH⁺)(m, 2H), 3.47 (d, J = 6.5 Hz, 1H), 3.30 (d, J = 12.8 Hz, 1H), 2.84-2.62(m, 1H), 2.48-2.16 (m, 4H), 2.03-1.91 (m, 1H), 1.86-1.60 (m, 3H), 1.15(t, J = 7.0 Hz, 3H). 99 ¹H NMR (400 MHz, METHANOL-d4) 8.06-7.89 (m, 1H),7.80- LC/MS: calc'd 7.67 (m, 1H), 7.35-7.20 (m, 2H), 7.19-7.05 (m, 1H),6.29- 583 (MH⁺), exp 6.13 (m, 1H), 4.56-4.38 (m, 1H), 4.13-4.00 (m, 2H),4.00- 583 (MH⁺) 3.89 (m, 1H), 3.34 (s, 2H), 2.79-2.61 (m, 1H), 2.51-2.17(m, 4H), 2.11-1.98 (m, 1H), 1.88-1.57 (m, 3H), 1.15 (t, J = 7.2 Hz, 3H).100 ¹H NMR (400 MHz, METHANOL-d4) 7.97-7.89 (m, 1H), 7.81- LC/MS: calc'd7.75 (m, 1H), 7.27-7.19 (m, 2H), 7.16-7.05 (m, 1H), 6.19- 567 (MH⁺), exp6.12 (m, 1H), 4.98-4.91 (m, 1H), 4.89-4.83 (m, 1H), 4.50 (s, 567 (MH⁺)1H), 4.14-4.02 (m, 2H), 3.93-3.85 (m, 1H), 3.70-3.62 (m, 1H), 3.60-3.56(m, 1H), 3.44-3.38 (m, 1H), 2.85-2.75 (m, 2H), 2.75-2.62 (m, 2H),2.60-2.49 (m, 1H), 1.71-1.58 (m, 1H). 101 ¹H NMR (400 MHz, METHANOL-d4)7.92 (s, 1H), 7.79 (d, J = LC/MS: calc'd 3.0 Hz, 1H), 7.23 (s, 2H),7.16-7.03 (m, 1H), 6.16 (s, 1H), 4.93- 567 (MH⁺), exp 4.85 (m, 1H),4.64-4.52 (m, 1H), 4.15-3.99 (m, 2H), 3.95- 567 (MH⁺) 3.83 (m, 1H),3.66-3.59 (m, 1H), 3.54 (s, 3H), 3.42-3.32 (m, 1H), 2.87-2.69 (m, 2H),2.69-2.59 (m, 1H), 2.59-2.45 (m, 1H), 1.73-1.56 (m, 1H), 1.35-1.05 (m,1H). 102 ¹H NMR (400 MHz, METHANOL-d4) 8.07-7.96 (m, 1H), 7.79- LC/MS:calc'd 7.66 (m, 1H), 7.48-7.34 (m, 2H), 7.32-7.14 (m, 2H), 6.30-563(MH⁺), exp 6.14 (m, 1H), 4.78-4.70 (m, 1H), 4.64-4.54 (m, 1H), 4.40-563(MH⁺) 4.24 (m, 1H), 4.15-3.81 (m, 4H), 3.81-3.70 (m, 1H), 3.51- 3.42(m, 1H), 3.12-2.98 (m, 1H), 2.96-2.73 (m, 3H), 2.64- 2.50 (m, 1H),2.49-2.39 (m, 1H), 1.52-1.37 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H). 103 ¹HNMR (400 MHz, METHANOL-d4) 8.02-7.90 (m, 1H), 7.73 LC/MS: calc'd (d, J =3.3 Hz, 1H), 7.42 (ddd, J = 1.6, 5.1, 7.3 Hz, 2H), 7.33- 563(MH⁺), exp7.14 (m, 2H), 6.22 (s, 1H), 4.75-4.67 (m, 1H), 4.65 (s, 1H), 563(MH⁺)4.59 (s, 2H), 4.57 (s, 1H), 4.23 (d, J = 17.6 Hz, 1H), 4.13-3.93 (m,4H), 3.78 (d, J = 11.3 Hz, 1H), 3.49 (d, J = 11.0 Hz, 1H), 3.11-2.96 (m,1H), 2.91 (d, J = 8.8 Hz, 1H), 2.87-2.73 (m, 2H), 2.62-2.39 (m, 2H),1.49-1.35 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H). 104 ¹H NMR (CD₃OD, 400MHz): ppm 8.51 (s, 0.5H), 8.45 (s, LC/MS: calc'd 0.5H), 7.99 (t, J = 3.2Hz, 1H), 7.78 (m, 1H), 7.42 (m, 1 H), 7.25 530 (MH⁺), exp (dd, J = 8.8,2.4 Hz, 1 H), 7.05 (m, 1H), 6.17 (s, 0.5H), 6.16 (s, 530 (MH⁺) 0.5H),4.15 (m, 3H), 3.95 (m, 3H), 3.70 (m, 1H), 3.54 (s, 1.5H), 3.52 (s,1.5H), 3.32 (m, 1H), 3.27 (m, 1H), 2.90 (m, 1H). 105 ¹H NMR (400 MHz,METHANOL-d4) 8.35 (s, 0.5H), 8.29 (s, LC/MS: calc'd 0.5H), 8.00 (t, J =3.2 Hz, 1H), 7.78 (dd, J = 2.4, 3.0 Hz, 1H), 530 (MH⁺), exp 7.45-7.41(m, 1H), 7.24 (dd, J = 2.4, 8.7 Hz, 1H), 7.09-7.02 (m, 530 (MH⁺) 1H),6.17 (s, 0.5H), 6.16 (s, 0.5H), 4.20-3.75 (m, 6H), 3.71- 3.58 (m, 1H),3.54 (s, 1.5H), 3.52 (s, 1.5H), 3.32-3.18 (m, 2H), 2.93-2.76 (m, 1H).106 ¹H NMR (400 MHz, METHANOL-d4) 8.50 (s, 0.6H), 8.44 (s, LC/MS: calc'd0.4H), 8.06-7.91 (m, 1H), 7.78 (dd, J = 1.8, 3.0 Hz, 1H), 7.52- 548(MH⁺), exp 7.35 (m, 1H), 7.24 (dd, J = 2.5, 8.8 Hz, 1H), 7.13-6.97 (m,548 (MH⁺) 1H), 6.18 (br, 1H), 5.86-5.59 (m, 1H), 4.51-4.20 (m, 1H),4.16-3.85 (m, 5H), 3.75-3.41 (m, 5H). 107 ¹H NMR (400 MHz, METHANOL-d4):8.15 (dd, J = 1.5, 3.0 LC/MS: calc'd Hz, 1H), 8.03 (dd, J = 3.0, 6.8 Hz,1H), 7.63 (d, J = 18.6 Hz, 565 (MH⁺), exp 1H), 7.55-7.52 (m, 1H),7.35-7.26 (m, 1H), 7.20-7.07 (m, 565 (MH⁺) 1H), 6.26 (s, 0.5H), 6.25 (s,0.5H), 4.46 (dd, J = 2.1, 17.4 Hz, 1H), 4.35-4.00 (m, 4H), 3.99-3.91 (m,1H), 3.73-3.59 (m, 1H), 3.55 (s, 1.5H), 3.52 (s, 1.5H), 3.49-3.37 (m,1H). 108 ¹H NMR (400 MHz, METHANOL-d4): 8.11 (dd, J = 1.1, 3.1 LC/MS:calc'd Hz, 1H), 8.02-7.94 (m, 1H), 7.56-7.53 (m, 1H), 7.31 (dd, J = 513(MH⁺), exp 2.6, 8.7 Hz, 1H), 7.21-7.07 (m, 1H), 6.25 (s, 1H), 4.47-4.26513 (MH⁺) (m, 2H), 4.18-3.91 (m, 3H), 3.80-3.61 (m, 5H), 3.59-3.43 (m,1H), 2.91-2.73 (m, 1H), 2.60-2.41 (m, 1H). 109 ¹H NMR (400 MHz,DMSO-d6): 9.87 (s, 1H), 7.96 (dd, J = 3.0, LC/MS: calc'd 16.8 Hz, 2H),7.51-7.34 (m, 2H), 7.18 (dt, J = 2.6, 8.5 Hz, 1H), 569 (MH⁺), exp 6.04(s, 1H), 4.23 (d, J = 17.3 Hz, 1H), 4.13 (d, J = 17.4 Hz, 569 (MH⁺) 1H),3.51 (s, 3H), 3.50 (br, 1H), 2.79-2.60 (m, 1H), 2.45-2.11 (m, 7H), 1.54(d, J = 13.8 Hz, 1H), 1.29 (dd, J = 3.5, 14.1 Hz, 1H). 110 ¹H NMR (400MHz, METHANOL-d4): 8.03 (d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.92 (d, J =3.0 Hz, 1H), 7.54 (dd, J = 6.0, 8.8 Hz, 1H), 7.30 569 (MH⁺), exp (dd, J= 2.6, 8.7 Hz, 1H), 7.12 (dt, J = 2.5, 8.4 Hz, 1H), 6.22 (s, 569 (MH⁺)1H), 4.85 (d, J = 17.3 Hz, 1H), 4.50 (d, J = 17.3 Hz, 1H), 4.15 (d, J =4.8 Hz, 2H), 3.65 (s, 3H), 3.10-2.94 (m, 1H), 2.84-2.56 (m, 6H), 2.07(d, J = 14.1 Hz, 1H), 1.81 (d, J = 14.6 Hz, 1H). 111 ¹H NMR (400 MHz,METHANOL-d4): 7.95 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.74 (d, J = 3.0Hz, 1H), 7.11-6.95 (m, 2H), 5.93 (s, 1H), 4.28 567 (MH⁺), exp (d, J =3.3 Hz, 2H), 3.62 (s, 2H), 3.56-3.48 (m, 1H), 2.86-2.63 567 (MH⁺) (m,2H), 2.61-2.33 (m, 8H), 2.32-2.20 (m, 2H), 1.76-1.66 (m, 1H), 1.40 (dd,J = 3.5, 14.3 Hz, 1H). 112 ¹H NMR (400 MHz, METHANOL-d4): 7.95 (d, J =3.0 Hz, LC/MS: calc'd 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.12-6.95 (m, 2H),5.94 (s, 1H), 567 (MH⁺), exp 4.52 (dd, J = 2.0, 17.8 Hz, 1H), 3.98 (d, J= 17.8 Hz, 1H), 3.62 567 (MH⁺) (s, 3H), 3.41-3.36 (m, 1H), 2.81-2.62 (m,2H), 2.60-2.29 (m, 7H), 2.28-2.12 (m, 2H), 1.74 (d, J = 10.8 Hz, 1H),1.34 (dd, J = 3.8, 14.1 Hz, 1H). 113 ¹H NMR (400 MHz, METHANOL-d4): 8.00(d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.80 (d, J = 3.0 Hz, 1H), 7.44 (t, J= 7.9 Hz, 1H), 7.28-7.14 569 (MH⁺), exp (m, 2H), 5.74 (s, 1H), 4.35-4.10(m, 2H), 3.70 (s, 3H), 3.44 (br, 569 (MH⁺) 1H), 3.24 (d, J = 11.8 Hz,1H), 2.84-2.65 (m, 2H), 2.55-2.30 (m, 4H), 2.29-2.16 (m, 1H), 1.69 (d, J= 13.8 Hz, 1H), 1.38 (dd, J = 4.8, 13.8 Hz, 1H). 114 ¹H NMR (400 MHz,METHANOL-d4): 8.00 (d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.81 (d, J = 3.0Hz, 1H), 7.29-7.08 (m, 3H), 5.73 (s, 1H), 4.31- 553 (MH⁺), exp 4.10 (m,2H), 3.70 (s, 3H), 3.43 (d, J = 6.0 Hz, 1H), 3.28 (d, J = 553 (MH⁺) 11.8Hz, 1H), 2.82-2.64 (m, 1H), 2.48-2.19 (m, 4H), 2.00- 1.91 (m, 1H),1.85-1.61 (m, 3H). 115 ¹H NMR (400 MHz, METHANOL-d4): 8.02 (d, J = 3.3Hz, 1H), LC/MS: calc'd 7.80 (d, J = 3.0 Hz, 1H), 7.32-7.04 (m, 3H), 5.73(s, 1H), 4.46 553 (MH⁺), exp (dd, J = 1.4, 17.7 Hz, 1H), 3.88 (d, J =17.8 Hz, 1H), 3.70 (s, 553 (MH⁺) 3H), 3.29 (br, 2H), 2.76-2.61 (m, 1H),2.45-2.18 (m, 4H), 2.02 (d, J = 12.8 Hz, 1H), 1.88-1.57 (m, 3H). 116 ¹HNMR (400 MHz, METHANOL-d4) Shift = 7.98 (d, J = 3.3 LC/MS: calc'd Hz,1H), 7.76 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 6.1, 8.7 Hz, 585 (MH⁺), exp1H), 7.24 (dd, J = 2.5, 8.8 Hz, 1H), 7.06 (dt, J = 2.8, 8.4 Hz, 585(MH⁺) 1H), 6.17 (s, 1H), 4.26 (s, 2H), 3.62 (s, 3H), 3.50 (br. s., 1H),3.27 (d, J = 12.8 Hz, 1H), 2.96-2.85 (m, 1H), 2.69-2.49 (m, 3H),2.33-2.15 (m, 3H), 1.94 (d, J = 13.3 Hz, 1H). 117 ¹H NMR (400 MHz,METHANOL-d4) Shift = 7.99 (d, J = 3.3 LC/MS: calc'd Hz, 1H), 7.75 (d, J= 3.3 Hz, 1H), 7.42 (dd, J = 6.3, 8.8 Hz, 585 (MH⁺), exp 1H), 7.24 (dd,J = 2.8, 8.8 Hz, 1H), 7.05 (dt, J = 2.8, 8.4 Hz, 585 (MH⁺) 1H), 6.18 (s,1H), 4.53 (dd, J = 2.0, 18.1 Hz, 1H), 3.95 (d, J = 17.8 Hz, 1H), 3.62(s, 3H), 3.40-3.35 (m, 1H), 3.31-3.23 (m, 1H), 2.95-2.80 (m, 1H), 2.53(s, 3H), 2.44-2.33 (m, 1H), 2.24 (d, J = 11.0 Hz, 2H), 1.90 (d, J = 13.8Hz, 1H). 118 ¹H NMR (400 MHz, METHANOL-d4) 7.95 (d, J = 3.0 Hz, 1H),LC/MS: calc'd 7.74 (d, J = 3.3 Hz, 1H), 7.11-6.94 (m, 2H), 5.93 (s, 1H),4.38- 583 (MH⁺), exp 4.16 (m, 2H), 3.63 (s, 3H), 3.50 (br. s., 1H), 3.26(br. s., 1H), 583 (MH⁺) 2.96-2.83 (m, 1H), 2.70-2.52 (m, 6H), 2.37-2.14(m, 3H), 1.93 (d, J = 14.6 Hz, 1H). 119 ¹H NMR (400 MHz, METHANOL-d4)ppm 7.95 (d, J = 3.3 Hz, LC/MS: calc'd 1H), 7.74 (d, J = 3.3 Hz, 1H),7.09-6.94 (m, 2H), 5.94 (s, 1H), 583 (MH⁺), exp 4.55 (dd, J = 2.4, 17.9Hz, 1H), 3.97 (d, J = 18.1 Hz, 1H), 3.63 583 (MH⁺) (s, 3H), 3.41-3.36(m, 1H), 3.31-3.27 (m, 1H), 2.94-2.79 (m, 1H), 2.57 (d, J = 2.5 Hz, 6H),2.41 (d, J = 14.8 Hz, 1H), 2.25 (br. s., 2H), 1.89 (d, J = 14.6 Hz, 1H).120 ¹H NMR (400 MHz, METHANOL-d4) 7.96 (d, J = 3.0 Hz, 1H), LC/MS:calc'd 7.76 (d, J = 3.0 Hz, 1H), 7.36-7.10 (m, 3H), 6.23 (s, 1H), 4.28585 (MH⁺), exp (s, 2H), 3.62 (s, 3H), 3.50 (br. s., 1H), 3.27 (br. s.,1H), 2.99- 585 (MH⁺) 2.83 (m, 1H), 2.65-2.57 (m, 3H), 2.36-2.14 (m, 3H),1.94 (d, J = 14.1 Hz, 1H). 121 ¹H NMR (400 MHz, METHANOL-d4) 7.96 (d, J= 3.3 Hz, 1H), LC/MS: calc'd 7.75 (d, J = 3.0 Hz, 1H), 7.34-7.11 (m,3H), 6.24 (s, 1H), 4.54 585 (MH⁺), exp (dd, J = 2.1, 17.9 Hz, 1H), 3.97(d, J = 17.8 Hz, 1H), 3.61 (s, 585 (MH⁺) 3H), 3.43-3.35 (m, 2H),2.94-2.80 (m, 1H), 2.67-2.46 (m, 3H), 2.40 (dd, J = 2.9, 14.2 Hz, 1H),2.26 (br. s., 2H), 1.97- 1.85 (m, 1H). 122 ¹H NMR (400 MHz,METHANOL-d4): 7.95 (dd, J = 3.1, 6.1 LC/MS: calc'd Hz, 1H), 7.76 (d, J =2.5 Hz, 1H), 7.48-7.39 (m, 1H), 7.24 (dd, 518 (MH⁺), exp J = 2.3, 8.8Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 6.18 (s, 1H), 4.31- 518 (MH⁺) 4.18(m, 1H), 4.12 (dd, J = 4.0, 17.6 Hz, 1H), 3.87 (dd, J = 4.5, 17.6 Hz,1H), 3.77-3.66 (m, 1H), 3.62-3.54 (m, 4H), 3.40 (br. s., 1H), 3.27 (br.s., 1H), 3.08 (t, J = 14.1 Hz, 1H), 2.17- 2.03 (m, 5H), 1.83-1.62 (m,2H). 123 ¹H NMR (400 MHz, METHANOL-d4) 8.03-7.94 (m, 1H), 7.79 LC/MS:calc'd (d, J = 2.8 Hz, 1H), 7.49-7.40 (m, 1H), 7.31-7.20 (m, 1H), 565(MH⁺), exp 7.13-7.01 (m, 1H), 6.17 (s, 1H), 4.85-4.67 (m, 1H), 4.46- 565(MH⁺) 4.33 (m, 1H), 4.28-4.11 (m, 2H), 4.05 (br. s., 1H), 3.84 (d, J =11.0 Hz, 2H), 3.68-3.60 (m, 3H), 3.24-3.11 (m, 1H), 2.98- 2.68 (m, 2H),2.61-2.50 (m, 1H), 2.42-2.26 (m, 1H), 2.25- 2.06 (m, 1H), 1.78 (br. s.,1H). 124 ¹H NMR (400 MHz, METHANOL-d4) 7.99 (dd, J = 3.1, 9.2 LC/MS:calc'd Hz, 1H), 7.74 (dd, J = 3.3, 5.0 Hz, 1H), 7.43 (ddd, J = 2.8, 6.0,565 (MH⁺), exp 8.8 Hz, 1H), 7.23 (dd, J = 2.5, 8.8 Hz, 1H), 7.11-6.98(m, 1H), 565 (MH⁺) 6.17 (d, J = 3.5 Hz, 1H), 4.74-4.49 (m, 1H),4.40-4.17 (m, 1H), 4.05-3.92 (m, 2H), 3.73-3.65 (m, 2H), 3.63 (d, J =1.5 Hz, 3H), 3.46-3.35 (m, 1H), 2.99-2.83 (m, 2H), 2.76 (br. s., 1H),2.67-2.43 (m, 2H), 2.36-2.23 (m, 1H), 1.49-1.36 (m, 1H). 125 ¹H NMR (400MHz, DMSO-d6) 9.77 (br. s., 1H), 8.04 (d, J = LC/MS: calc'd 3.1 Hz, 1H),7.95 (d, J = 3.1 Hz, 1H), 7.48-7.36 (m, 2H), 7.16 585 (MH⁺), exp (dt, J= 2.6, 8.5 Hz, 1H), 6.04 (s, 1H), 4.55 (dd, J = 2.3, 17.6 585 (MH⁺) Hz,1H), 4.08 (d, J = 17.4 Hz, 1H), 3.99-3.84 (m, 3H), 3.79 (d, J = 11.2 Hz,1H), 3.52 (s, 3H), 3.19 (d, J = 10.4 Hz, 2H), 2.71- 2.61 (m, 2H), 2.15(dd, J = 9.4, 15.8 Hz, 1H), 1.99-1.82 (m, 2H). 126 ¹H NMR (400 MHz,CDCl₃) 9.80-9.66 (m, 1H), 7.88 (d, J = LC/MS: calc'd 3.0 Hz, 1H), 7.48(d, J = 3.1 Hz, 1H), 7.28-7.23 (m, 1H), 7.15 585 (MH⁺), exp (dd, J =2.6, 8.6 Hz, 1H), 6.92 (dt, J = 2.6, 8.3 Hz, 1H), 6.21 (s, 585 (MH⁺)1H), 4.52-4.39 (m, 1H), 4.35-4.26 (m, 1H), 4.16 (d, J = 10.3 Hz, 1H),4.10-3.97 (m, 2H), 3.93-3.87 (m, 1H), 3.63 (s, 3H), 3.53-3.36 (m, 1H),3.04-2.83 (m, 2H), 2.71 (br. s., 1H), 2.42 (dd, J = 9.9, 16.3 Hz, 1H),2.15 (d, J = 7.7 Hz, 2H). 127 ¹H NMR (400 MHz, METHANOL-d4) 7.97 (d, J =3.3 Hz, 1H), LC/MS: calc'd 7.75 (d, J = 3.0 Hz, 1H), 7.12-6.96 (m, 2H),5.93 (s, 1H), 4.86- 596 (MH⁺), exp 4.76 (m, 1H), 4.19-3.99 (m, 6H), 3.87(d, J = 11.0 Hz, 1H), 596 (MH⁺) 3.52-3.37 (m, 1H), 3.07 (d, J = 10.0 Hz,1H), 2.82 (dd, J = 3.8, 15.8 Hz, 1H), 2.67 (br. s., 1H), 2.57 (d, J =2.3 Hz, 3H), 2.26 (dd, J = 9.9, 15.9 Hz, 1H), 2.06 (d, J = 7.5 Hz, 2H),1.18 (t, J = 7.2 Hz, 3H). 128 ¹H NMR (400 MHz, METHANOL-d4) 7.97 (d, J =3.3 Hz, 1H), LC/MS: calc'd 7.75 (d, J = 3.0 Hz, 1H), 7.09-6.98 (m, 2H),5.93 (s, 1H), 4.54- 596 (MH⁺), exp 4.32 (m, 2H), 4.17-4.04 (m, 4H),4.01-3.81 (m, 2H), 3.51- 596 (MH⁺) 3.37 (m, 1H), 3.01 (d, J = 10.8 Hz,1H), 2.88-2.73 (m, 2H), 2.57 (d, J = 2.5 Hz, 3H), 2.30 (dd, J = 9.8,15.8 Hz, 1H), 2.13 (d, J = 7.5 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H). 129 ¹HNMR (400 MHz, METHANOL-d4) 7.98 (d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.76(d, J = 3.3 Hz, 1H), 7.27 (d, J = 1.8 Hz, 2H), 7.21-7.10 599 (MH⁺), exp(m, 1H), 6.24 (s, 1H), 4.86-4.73 (m, 1H), 4.20-4.12 (m, 1H), 599 (MH⁺)4.11-3.99 (m, 5H), 3.88 (d, J = 11.0 Hz, 1H), 3.51-3.37 (m, 1H),3.12-3.02 (m, 1H), 2.80 (d, J = 3.8 Hz, 1H), 2.70 (br. s., 1H),2.33-2.20 (m, 1H), 2.06 (d, J = 9.3 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H).130 ¹H NMR (400 MHz, METHANOL-d4) 7.98 (d, J = 3.3 Hz, 1H), LC/MS:calc'd 7.76 (d, J = 3.3 Hz, 1H), 7.33-7.21 (m, 2H), 7.16 (dd, J = 1.6,599 (MH⁺), exp 9.2 Hz, 1H), 6.24 (s, 1H), 4.43 (d, J = 8.0 Hz, 2H),4.16-4.00 599 (MH⁺) (m, 4H), 3.98-3.82 (m, 2H), 3.53-3.36 (m, 1H), 3.02(d, J = 10.5 Hz, 1H), 2.90-2.75 (m, 2H), 2.31 (dd, J = 9.8, 15.8 Hz,1H), 2.13 (d, J = 7.0 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 131 ¹H NMR (400MHz, METHANOL-d4) 7.98 (d, J = 3.0 Hz, 1H), LC/MS: calc'd 7.76 (d, J =3.0 Hz, 1H), 7.27-7.16 (m, 2H), 6.17 (s, 1H), 4.82- 603 (MH⁺), exp 4.72(m, 1H), 4.43 (d, J = 18.6 Hz, 1H), 4.19-3.86 (m, 4H), 603 (MH⁺) 3.62(s, 3H), 3.51-3.37 (m, 1H), 3.10-2.96 (m, 1H), 2.90- 2.65 (m, 2H),2.35-2.20 (m, 1H), 2.17-2.02 (m, 2H). 132 ¹H NMR (400 MHz, METHANOL-d4)7.96 (d, J = 3.3 Hz, 1H), LC/MS: calc'd 7.74 (d, J = 3.3 Hz, 1H), 7.03(d, J = 6.3 Hz, 2H), 5.93 (s, 1H), 582 (MH⁺), exp 4.55-4.44 (m, 1H),4.42-4.33 (m, 1H), 4.16-4.01 (m, 2H), 582 (MH⁺) 3.89 (s, 2H), 3.63 (s,3H), 3.51-3.36 (m, 1H), 3.00 (d, J = 10.8 Hz, 1H), 2.88-2.74 (m, 2H),2.57 (d, J = 2.3 Hz, 3H), 2.31 (dd, J = 9.8, 15.8 Hz, 1H), 2.13 (d, J =8.5 Hz, 2H). 133 ¹H NMR (METHANOL-d4, 400 MHz): 7.98 (d, 1H), 7.77 (d,LC/MS: exp 506 1H), 7.40-7.48 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 6.18(d, [M + H]⁺) 1H), 4.42-4.53 (m, 1H), 4.10-4.18 (m, 1H), 4.00-4.10 (m,2H), 3.87-4.00 (m, 3H), 3.65 (d, 3H), 3.41-3.52 (m, 2H), 2.18-2.25 (m,1H). 134 ¹H NMR (METHANOL-d4, 400 MHz): 7.93-8.01 (m, 1H), 7.75 LC/MS:calc'd (d, 1H), 7.61 (m, 1H), 7.37-7.45 (m, 1H), 7.32 (m, 1H), 7.16 (m,576 (MH⁺), exp 1H), 6.19 (s, 1H), 4.62 (d, 1H), 4.23 (d, 1H), 3.96-4.09(m, 2H), 576(MH⁺) 3.62 (s, 3H), 3.56 (d, 2H), 2.90-3.02 (m, 2H),2.62-2.71 (m, 1H), 2.49-2.54 (m, 2H), 2.38-2.49 (m, 2H), 1.44-1.57 (m,2H). 135 ¹H NMR (METHANOL-d4, 400 MHz): 8.02 (d, 1H), 7.92 (d, LC/MS:calc'd 1H), 7.35-7.44 (m, 1H), 7.30 (m, 1H), 6.21 (s, 1H), 5.03 (d, 1H),567 (MH⁺), exp 4.71 (d, 1H), 4.14-4.26 (m, 2H), 3.85 (br. s., 1H), 3.76(d, 1H), 567(MH⁺) 3.71 (br. s., 1H), 3.67 (s, 3H), 2.68 (m, 6H), 1.90(d, 2H). 136 ¹H NMR (METHANOL-d4, 400 MHz): 8.04 (d, 1H), 7.93 (d,LC/MS: calc'd 1H), 7.44-7.54 (m, 1H), 7.16-7.35 (m, 2H), 5.72 (s, 1H),5.05 (d, 549 (MH⁺), exp 1H), 4.64 (d, 1H), 4.11-4.26 (m, 2H), 3.77-3.92(m, 1H), 3.67- 549(MH⁺) 3.76 (m, 4H), 3.64 (d, 1H), 2.50-2.76 (m, 5H),1.88 (d, 2H). 137 ¹H NMR (METHANOL-d4, 400 MHz): 7.94-8.03 (m, 1H), 7.76LC/MS: calc'd (d, 1H), 7.38-7.47 (m, 1H), 7.38-7.47 (m, 1H), 7.24 (m,1H), 609 (MH⁺), exp 7.06 (m, 1H), 6.17 (s, 1H), 4.49-4.63 (m, 1H),4.22-4.33 (m, 609 (MH⁺) 2H), 4.05-4.18 (m, 2H), 3.66-3.80 (m, 2H), 3.63(s, 3H), 2.91 (br. s., 1H), 2.39 (br. s., 1H), 1.98-2.31 (m, 5H), 1.63(br. s., 1H), 1.33-1.36 (m, 3H). 138 ¹H NMR (METHANOL-d4, 400 MHz):7.93-8.03 (m, 1H), 7.83 LC/MS: calc'd (br. s., 1H), 7.44-7.56 (m, 1H),7.26 (m, 1H), 7.09 (m, 1H), 6.18 609 (MH⁺), exp (s, 1H), 5.00 (br. s.,1H), 4.61 (br. s., 2H), 4.20 (m, 5H), 3.71- 609(MH⁺) 3.86 (m, 1H), 3.65(s, 3H), 3.52 (m, 1H), 2.83-2.97 (m, 1H), 2.72-2.83 (m, 1H), 2.60-2.72(m, 1H), 2.00-2.20 (m, 1H), 1.33- 1.51 (m, 1H), 1.30 (m, 3H). 139 ¹H NMR(METHANOL-d4, 400 MHz): 7.98 (d, 1H), 7.78 (d, LC/MS: calc'd 1H), 7.44(m, 1H), 7.25 (m, 1H), 7.05 (m, 1H), 6.18 (s, 1H), 550 (MH⁺), exp 4.69(d, 1H), 4.08-4.26 (m, 3H), 3.87-3.98 (m, 2H), 3.65 (s, 550 (MH⁺) 3H),3.09 (br. s., 1H), 2.94-3.07 (m, 3H), 2.25-2.25 (m, 1H), 2.14-2.25 (m,1H), 2.00-2.11 (m, 1H). 140 1H NMR (METHANOL-d4, 400 MHz): 7.98-8.08 (m,1H), 7.90 LC/MS: calc'd (d, 1H), 7.07-7.27 (m, 3H), 6.10 (s, 1H), 4.69(d, 1H), 4.19-4.29 548 (MH⁺), exp (m, 2H), 4.06-4.19 (m, 3H), 3.95 (m,2H), 3.19 (d, 1H), 3.09- 548(MH⁺) 3.17 (m, 1H), 2.99 (m, 2H), 1.92-2.06(m, 2H), 1.14-1.26 (m, 3H). 141 ¹H NMR (METHANOL-d4, 400 MHz): 8.04 (d,1H), 7.91 (d, LC/MS: calc'd 1H), 7.42-7.56 (m, 2H), 7.14 (m, 1H), 6.23(s, 1H), 4.71 (d, 1H), 609 (MH⁺), exp 4.18-4.30 (m, 3H), 4.05-4.17 (m,2H), 3.96 (m, 2H), 3.19-3.26 609(MH⁺) (m, 1H), 3.15 (d, 1H), 2.94-3.05(m, 2H), 1.92-2.08 (m, 2H), 1.19 (m, 3H). 142 1H NMR (METHANOL-d4, 400MHz): 7.95(d, J = 4.0 Hz, 1 LC/MS: calc'd H), 7.77 (d, J = 4.0 Hz, 1H),7.42 (m, 1 H), 7.25 (m, 1H), 7.08 477 (MH⁺), exp (m, 1 H), 6.16 (s, 1H), 4.32~4.39 (m, 2H), 4.03-3.98 (d, J = 477 (MH⁺) 3H, 1H), 3.84-3.80(d, J = 16 Hz, 1H), 3.60 (s, 3H), 2.80-2.28 (m, 6 H), 2.00(m, 2H). 143¹H NMR (METHANOL-d4, 400 MHz): 7.93(d, J = 4.0 Hz, 1 LC/MS: calc'd H,7.74 (d, J = 4.0 Hz, 1H), 7.43 (m, 1 H), 7.25 (m, 1H), 7.08 497 (MH⁺),exp (m, 1 H), 6.17 (s, 1 H), 4.47~4.36 (m, 1H), 4.18~4.11 (m, 1H), 497(MH⁺) 3.61 (s, 3H), 3.37 (m, 1H), 3.0 (m, 1 H), 2.74-2.61 (m, 2H), 2.10(m, 1H), 1.92~1.80(m, 3H). 144 ¹H NMR (METHANOL-d4, 400 MHz): 7.94(d, J= 4.0 Hz, 1 LC/MS: calc'd H), 7.76 (d, J = 4.0 Hz, 1H), 7.42 (m, 1 H),7.25 (m, 1H), 7.08 497 (MH⁺), exp (m, 1 H), 6.15 (s, 1 H), 4.37~3.94 (m,2H), 3.61 (s, 3H), 3.34 497 (MH⁺) (m, 1H), 3.09~2.75 (m, 3 H), 2.36 (m,1H), 2.04~1.92(m, 3H). 145 ¹H NMR (METHANOL-d4, 400 MHz): 7.94(d, J =4.0 Hz, 1 LC/MS: calc'd H), 7.75 (d, J = 4.0 Hz, 1H), 7.42 (m, 1 H),7.25 (m, 1H), 7.08 534 (MH⁺), exp (m, 1 H), 6.15 (s, 1 H), 4.30~4.14 (m,3H), 3.87-3.85 (m, 3H), 534 (MH⁺) 3.65-3.55 (m, 6H), 3.06-3.04 (d, J = 8Hz, 1H), 2.75-2.72 (d, J = 12 Hz, 1 H), 2.05-2.03(d, J = 8 Hz, 1H), 1.99(s, 3H), 1.79- 1.76(d, J = 12 Hz, 1H), 1.29 (m, 1H). 146 ¹H NMR(METHANOL-d4, 400 MHz): 7.99 (d, J = 4.0 Hz, 1 LC/MS: calc'd H), 7.77(d, J = 4.0 Hz, 1H), 7.42 (m, 1 H), 7.24 (m, 1H), 7.04 670 (MH⁺), exp(m, 1 H), 6.17 (s, 1 H), 4.53~4.49 (d, J = 16 Hz, 1H), 4.25~4.20 670(MH⁺) (m, 2H), 4.17~4.14 (m, 2H), 4.06~4.02 (d, J = 16 Hz, 1H),4.00~3.93 (m, 2H), 3.65 (s, 3 H), 3.12 (s, 2H), 3.08 (s, 3H), 2.90 (m,2H), 2.50 (m, 2H), 2.18~2.15 (t, J1 = 16 Hz, J2 = 28 Hz, 2H), 1.31 (t,J1 = 8 Hz, J2 = 16 Hz, 3H). 147 ¹H NMR (METHANOL-d4, 400 MHz): 7.99 (d,J = 4.0 Hz, 1 LC/MS: calc'd H), 7.77 (d, J = 4.0 Hz, 1H), 7.42 (m, 1 H),7.24 (m, 1H), 7.04 688 (MH⁺), exp (m, 1 H), 6.17 (s, 1 H), 4.52~4.57 (d,J = 16 Hz, 1H), 4.19~4.10 688 (MH⁺) (m, 2H), 4.08~4.03 (m, 2H),3.85~3.80 (m, 2H), 3.83 (s, 3 H), 3.16 (s, 2H), 3.08 (s, 3H), 2.80 (m,2H), 2.46 (m, 2H), 2.32 (m, 2H), 1.28 (t, J1 = 4 Hz, J2 = 12 Hz, 3H).148 ¹H NMR (METHANOL-d4, 400 MHz): 8.09(d, J = 4.0 Hz, 1 LC/MS: calc'dH), 8.06 (d, J = 4.0 Hz, 1H), 7.66 (m, 1 H), 7.30 (m, 1H), 7.10 541(MH⁺), exp (m, 1 H), 6.24 (s, 1 H), 4.22 (m, 2H), 3.74 (m, 1H), 3.64 (s,3H), 541 (MH⁺) 2.69-2.60 (m, 1H), 2.33-2.20(m, 2 H), 2.08-2.01(m, 3H).149 ¹H NMR (METHANOL-d4, 400 MHz): 8.03(d, J = 4.0 Hz, 1 LC/MS: calc'dH), 7.90 (d, J = 4.0 Hz, 1H), 7.55 (m, 1 H), 7.28 (m, 1H), 7.10 541(MH⁺), exp (m, 1 H), 6.22 (s, 1 H), 4.29~4.15 (m, 2H), 3.75 (m, 1H),3.63 541 (MH⁺) (s, 3H), 2.62-2.71 (m, 1H), 2.33-2.15(m, 3 H),2.07-2.02(m, 2H). 150 ¹H NMR (400 MHz, METHANOL-d4) d ppm 8.04 (d, J =3.26 LC/MS: calc'd Hz, 1 H), 7.95 (d, J = 3.26 Hz, 1 H), 7.15-7.38 (m, 3H), 6.29 569 (MH⁺), exp (s, 1 H), 4.51-4.71 (m, 2 H), 3.92-4.23 (m, 4H), 3.12 (m, 2 H), 569 (MH⁺) 2.21-2.75(m, 4 H), 1.13(m, 3H). 151 ¹H NMR(METHANOL-d4, 400 MHz): 7.99(d, J = 4.0 Hz, 1 LC/MS: calc'd H), 7.82 (d,J = 4.0 Hz, 1H), 7.51 (m, 1 H), 7.27 (m, 1H), 7.11 541 (MH⁺), exp (m, 1H), 6.17 (s, 1 H), 4.29~4.33 (m, 1H), 4.04~4.10 (m, 2H), 541 (MH⁺) 3.75(m, 1H), 3.63 (s, 3 H), 2.91(m, 1H), 2.54~2.01 (m, 4H). 152 ¹H NMR(METHANOL-d4, 400 MHz): 7.95(d, J = 4.0 Hz, 1 LC/MS: calc'd H), 7.78 (d,J = 4.0 Hz, 1H), 7.49 (m, 1 H), 7.27 (m, 1H), 7.08 541 (MH⁺), exp (m, 1H), 6.18 (s, 1 H), 4.35~4.01 (m, 2H), 4.04~4.10 (m, 2H), 541 (MH⁺) 3.86(m, 1H), 3.61 (s, 3 H), 3.40(m, 1H), 2.40~2.01 (m, 5H).

TABLE 2 Anti-HBV activity data of particular compounds in HepG2.2.15cells Example EC₅₀ Example EC₅₀ Example EC₅₀ No. (μM) No. (μM) No. (μM)1 0.059 2 0.1143 3 0.4002 4 0.039 5 0.021 6 0.032 7 0.012 9 0.014 100.0088 11 0.0066 12 0.566 13 0.27 14 0.013 15 0.043 16 0.015 17 0.004 180.020 19 0.004 20 0.035 21 0.020 23 0.3675 24 0.013 25 0.0145 26 0.01327 0.2541 28 0.015 29 0.0343 30 0.011 31 0.035 32 0.032 33 0.011 340.042 35 0.006 36 0.003 38 0.1145 39 0.032 40 0.032 41 0.1326 42 0.054543 0.003 45 0.0005 46 0.0866 47 0.2952 48 0.0194 49 0.0172 50 0.0241 510.0149 52 0.0179 53 0.0168 54 0.0082 55 0.0223 56 0.0044 57 0.0219 580.0114 59 0.0156 60 0.0016 61 0.0048 62 0.007 63 0.0015 64 0.0166 650.0118 66 0.0036 67 0.004 68 0.0038 69 0.0031 70 0.0082 71 0.003 720.0132 73 0.003 74 0.0109 75 0.0291 76 0.031 77 0.014 78 0.002 79 0.293380 0.0017 81 0.0405 82 0.0131 83 0.0086 84 0.0376 85 0.0066 86 0.002 870.0394 88 0.0013 89 0.0305 90 0.0035 91 0.0907 92 0.0015 93 0.0289 940.0217 95 0.0311 96 0.0068 97 0.1558 98 0.0007 99 0.0126 100 0.2829 1010.024 102 0.066 103 0.2738 104 0.0048 105 0.0027 106 0.0085 107 0.0021108 0.0074 109 0.0017 110 0.0443 111 0.0012 112 0.0358 113 0.0091 1140.0063 115 0.1627 116 0.0073 117 0.0402 118 0.005 119 0.0213 120 0.0096121 0.033 122 0.0774 123 0.0357 124 0.2956 125 0.0261 126 0.0103 1270.0161 128 0.0025 129 0.021 130 0.0064 131 0.0057 132 0.0103 133 0.034134 0.021 135 0.0065 136 0.102 137 0.0032 138 0.0582 139 0.172 140 0.103141 0.271 142 0.13 143 0.041 144 0.094 145 0.017 146 0.0005 147 0.0009148 0.0592 149 0.004 150 0.0077 151 0.0295 152 0.0177

More particular compounds of formula I include the following:

-   9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   8-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylic    acid;-   (R)-6-(7-Carbamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-sulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2-hydroxy-acetyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-4-(2-Bromo-4-fluoro-phenyl)-6-(7-carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-10-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-(7-Acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic    acid;-   6-(7-Carboxymethyl-3-thia-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-4-(2-Chloro-4-fluoro-phenyl)-6-(9-oxa-3,4,11-triaza-tricyclo[5.3.1.0*2,6*]undeca-2(6),4-dien-11-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   2-[[(1R,5S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]acetic    acid;-   2-[[8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]oxy]acetic    acid;-   8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylic    acid;-   Methyl    (4R)-4-(2-bromo-4-fluoro-phenyl)-6-[(7-carbamoyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-endo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   2-[(1R,5S,6S)-8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Exo-2-[(1S,5R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   (1S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   (1R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1R,3S,5S)-8-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(1S,3R,5R)-8-[[(4S)-4-(3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(3S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]acetic    acid;-   2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   (1S,4R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylic    acid;-   (1R,4S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylic    acid;-   8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   2-[(7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid; and-   2-[(7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetic    acid.

Compound with favorable pharmacokinetics is more likely to beefficacious and safe. It is very important for a drug to have a moderateor low clearance and a reasonable half-life, as this often leads to agood oral bioavailability and high systemic exposure. Reducing theclearance of a compound or drug could reduce the daily dose required forefficacy and therefore give a better efficacy and safety profile. Asshown in Table 3, compounds of the present invention show low humanmicrosomal clearance.

Results of human microsomal clearance data of particular compounds aregiven in Table 3.

TABLE 3 Human microsomal clearance data of particular compounds CLh CLhCLh Example (mL/min/ Example (mL/min/ Example (mL/min/ No. Kg) No. Kg)No. Kg) 1 3.0 2 3.2 3 0 5 0 6 0.5 8 0 11 9.0 18 1.3 19 4.6 21 4.3 23 7.124 2.6 26 3.5 28 0.6 29 1.7 35 6.4 36 7.8 39 7.4 40 1.4 44 7.1 46 4.0 484.8 50 1.4 52 2.7 53 7.0 54 6.5 55 0 56 6.1 57 5.0 58 2.1 59 2.1 60 6.461 6.3 62 4.6 63 4.1 64 2.6 65 2.8 66 3.2 67 2.9 68 3.5 69 2.4 72 2.8 733.6 74 0.5 75 1.0 76 3.3 77 1.3 78 1.9 79 3.5 80 4.6 81 0 82 0 83 1.6 840 85 1.3 86 0 87 0 88 0.2 89 0 90 1.5 91 5.1 92 1.7 93 0.2 94 0 95 0 961.8 97 0 98 4.5 99 3 100 0 101 0 102 3.0 103 0 109 7.2 110 4.1 111 4.8113 6.2 114 1.2 115 4.6 116 2.6 117 1.8 118 3.1 120 0 122 7.0 123 3.0124 4.2 125 0 126 0 127 2.9 128 3.8 129 2.0 130 5.0 131 0 132 2.6 1341.7 135 4.2 136 5.5 139 5.1 148 2.3 149 3.4 150 3.1

The aqueous solubility is an important physico-chemical property thatplays a significant role in various physical and biological processes.It is desirable to have good solubility which enables good permeabilityand gastric and intestinal absorption, linear dose proportionality, lessPK variability, and easy formulation for PD/PK studies. At differentstages of the drug discovery/development process solubility has to bedetermined and especially in the early phases (lead generation to leadoptimization) high throughput methods are needed. Lyophilisationsolubility assay (Lysa) is a well adopted high throughput assay tomeasure compound solubility in industry.

Results of Lysa are given in Table 4.

TABLE 4 Solubility data of particular compounds Example Lysa ExampleLysa Example Lysa No. (μg/mL) No. (μg/mL) No. (μg/mL) 1 540 2 450 3 >6785 >660 6 >665 10 435 12 >597 13 313 15 233 23 573 24 >621 26 470 28 >65529 >600 33 100 34 263 39 >610 40 >634 41 >552 42 188 44 >623 46 >685 48100 50 >724 52 >630 53 163 54 119 55 505 58 >701 59 >732 64 660 65 37566 390 67 319 68 320 69 203 72 640 73 >654 74 >621 75 >656 76 >706 77491 78 111 79 >745 80 221 81 >673 82 >628 83 564 84 >643 85 >639 86 14988 120 90 230 101 580 102 410 103 345 109 107 114 224 115 128 116 495118 112 120 317 123 >753 124 >753 125 170 126 >605 130 219 131 261 132330 134 >695 135 533 136 485 139 >610 145 585 148 >655 149 >665

Based on FDA guidance, in order to support clinical testing in humans,the assessment of acceptable risk-benefit has to be achieved byproviding clear evidence of in vitro antiviral activity (EC₅₀) andcytotoxicity (CC₅₀). It is important to establish that aninvestigational product has antiviral activity at concentrations thatcan be achieved in vivo without inducing toxic effects to cells.Furthermore, in a cell culture model, apparent antiviral activity of aninvestigational product can be the result of host cell death afterexposure to the product. The relative effectiveness of the compound ininhibiting viral replication compared to inducing cell death is definedas the selectivity index (CC₅₀ value/EC₅₀ value). It is desirable tohave a high selectivity index giving maximum antiviral activity withminimal cell toxicity.

Results of CC₅₀ and the corresponding selectivity index are given inTable 5.

TABLE 5 CC₅₀ and selectivity index of particular compounds SelectivitySelectivity Example CC₅₀ index Example CC₅₀ index No. (μM) (CC₅₀/EC₅₀)No. (μM) (CC₅₀/EC₅₀) 7 >100 >8333 10 >100 >11364 11 >100 >1515214 >100 >7692 17 50 11628 19 58 16571 24 >100 >7692 25 >100 >6897 26 685231 28 >100 >9804 33 >100 >9091 35 50 7813 36 38 11875 39 >100 >5848 4343 14845 45 43 85280 52 >100 >5587 54 60 7300 56 43 9766 58 >100 >877259 >100 >6410 60 34 21169 61 53 10942 62 46 6571 63 34 2236764 >100 >6024 65 71 5980 67 >100 >25000 69 >100 >32258 70 60 7268 71 4414690 72 >100 >7576 73 72 24083 74 >100 >9174 77 >100 >7143 78 73 3651580 38 22394 82 >100 >7634 83 65 7558 85 >100 >15152 88 52 39662 104 449079 105 33 12041 107 26 12495 108 74 9953 109 >100 >58824 111 79 65983113 58 6404 116 >100 >13699 118 45 8960 120 87 9083 126 >100 >9709 12835 14056 130 69 10830 131 53 9346 135 >100 >15385 137 55 17031145 >100 >5882 146 >100 >200000 147 >100 >111111 152 >100 >5650

TABLE 6 Relative induction values of particular compounds to 10 μMrifampicin Example % of Positive control No. (10 μM Rifampicin) 12 21 2429 26 36 31 25 35 20 38 35 48 17 56 23 66 6.2 68 7.7 69 21 73 21 80 3588 39 90 37 126 17 135 27

Synthesis

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsas well as their starting materials are provided in the schemes belowand in the examples. All substituents, in particular, R¹ to R⁴ are asdefined above unless otherwise indicated. Furthermore, and unlessexplicitly otherwise stated, all reactions, reaction conditions,abbreviations and symbols have the meanings well known to a person ofordinary skill in organic chemistry.

General Synthetic Route for Compound Ia (Scheme 1)

Compound of interest Ia can be prepared according to Scheme 1. A one-potreaction between acetyl acetate II, aldehyde III and thiazole amidine IVgives dihydropyrimidine V. (−)-Enantiomer Va is then obtained by SFCchiral separation of V. The absolute stereochemistry of one specificcompound B1 is determined by X-ray diffraction study (FIG. 1) and othersare assigned based on comparison of SFC retention time. Bromination ofVa affords VIa. Coupling VIa with a suitable bridged amine VII gives thecompound of interest Ia.

Dihydropyrimidine V can be prepared from condensation and cyclizationsequence of acetyl acetate II, aldehyde III and thiazole amidine IV. Thereaction can be carried out in a suitable alcoholic solvent such astrifluoroethanol in the presence of a base such as potassium acetateunder a heating condition over several hours.

(−)-Enantiomer Va is obtained by SFC chiral separation of V.

Bromide VIa can be prepared by reaction of Va with a bromination reagentsuch as N-bromosuccinimide, in a suitable inert solvent such as carbontetrachloride at 80-100 degrees Celsius for about 1 hour.

Compound of interest Ia can be obtained by coupling bromide VIa withbridged amine VII. The reaction is typically performed in a suitablesolvent such as 1,2-dichloroethane at room temperature over severalhours in the presence of an organic base such asN,N-diisopropylethylamine.

An alternative general synthetic route for compounds I, Ia and Ib(Scheme 2)

Compounds of interest I, Ia and Ib can be prepared according to Scheme2. Starting with acetyl acetate II, aldehyde III and thiazole amidineIV, dihydropyrimidine V can be synthesized through a one-potcondensation reaction. Bromination of Compound V affords bromide VI.Coupling bromide VI with bridged amine VII generates compound ofinterest I. Further chiral separation of I affords two enantiomericallypure compounds of interest Ia and Ib.

Dihydropyrimidine V can be prepared from condensation and cyclizationsequence of acetyl acetate II, aldehyde III and thiazole amidine IV. Thereaction can be carried out in a suitable alcoholic solvent such astrifluoroethanol in the presence of a base such as potassium acetateunder a heating condition over several hours.

Bromide VI can be prepared by reaction of V with a bromination reagentsuch as N-bromosuccinimide in a suitable inert solvent such as carbontetrachloride at 80-100 degrees Celsius for about 1 hour.

Compound of interest I can be obtained by coupling bromide VI withbridged amine VII.

The reaction is typically performed in a suitable solvent such as1,2-dichloroethane at room temperature over several hours in thepresence of an organic base such as N,N-diisopropylethylamine.

Compounds of further interest Ia and Ib are obtained by preparative HPLCseparation of diastereomeric mixture I. The stereochemistry of Ia isassigned based on the comparison of its analytical data with thecompound made by synthetic route A.

This invention also relates to a process for the preparation of acompound of formula I comprising the reaction of

(a) a compound of formula (A)

with bridged amine in the presence of a base;(b) a compound of formula (B)

under chiral separation condition;wherein R¹ to R⁴ are defined above unless otherwise indicated.

In step (a), the base can be for example N,N-diisopropylethylamine.

A compound of formula I when manufactured according to the above processis also an object of the invention.

Pharmaceutical Compositions and Administration

The invention also relates to a compound of formula I for use astherapeutically active substance.

Another embodiment provides pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of formula I may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, butpreferably ranges anywhere from about 3 to about 8. In one example, acompound of formula I is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of formula I are sterile. The compoundmay be stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularhuman being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “effective amount” of the compoundto be administered will be governed by such considerations, and is theminimum amount necessary to the suppression of serum HBV DNA levels, orHBeAg seroconversion to HBeAb, or HBsAg loss, or normalization ofalanine aminotransferase levels and improvement in liver histology. Forexample, such amount may be below the amount that is toxic to normalcells, or the human as a whole.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 0.1 to about1000 mg of the compound of the invention.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

An example of a suitable oral dosage form is a tablet containing about0.1 mg to 1000 mg of the compound of the invention compounded with about90 mg to 30 mg anhydrous lactose, about 5 mg to 40 mg sodiumcroscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, andabout 1 mg to 10 mg magnesium stearate. The powdered ingredients arefirst mixed together and then mixed with a solution of the PVP. Theresulting composition can be dried, granulated, mixed with the magnesiumstearate and compressed to tablet form using conventional equipment. Anexample of an aerosol formulation can be prepared by dissolving thecompound, for example 5 mg to 400 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such sodium chloride, if desired. The solution may be filtered,e.g., using a 0.2 micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodimentincludes a pharmaceutical composition comprising a compound of FormulaI, or a stereoisomer or pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or excipient.

Indications and Methods of Treatment

The compounds of the invention can inhibit HBV's de novo DNA synthesisand reduce HBV DNA levels. Accordingly, the compounds of the inventionare useful for the treatment or prophylaxis of HBV infection.

The invention relates to the use of a compound of formula I for thetreatment or prophylaxis of HBV infection.

The use of a compound of formula I for the preparation of medicamentsuseful in the treatment or prophylaxis diseases that are related to HBVinfection is an object of the invention.

The invention relates in particular to the use of a compound of formulaI for the preparation of a medicament for the treatment or prophylaxisof HBV infection.

Another embodiment includes a method for the treatment or prophylaxis ofHBV infection in a human in need of such treatment, wherein the methodcomprises administering to said human a therapeutically effective amountof a compound of Formula I, a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof

Combination Therapy

The compounds of the invention can be used together with interferon,pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir,Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxisof HBV.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1. X-ray crystal structure of compound B1

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Abbreviations used herein are as follows:

-   -   [α]_(D) ²⁰: specific optical rotation at 20 degrees Celsius    -   ACN acetonitrile    -   n-BuLi: n-butyl lithium    -   t-BuOH: tert-butyl alcohol    -   calc'd: calculated    -   CbzCl: benzyl chloroformate    -   CC₅₀: concentration results in the death of 50 percent of the        cells    -   CCK-8: cell counting kit-8    -   CCl₄: carbon tetrachloride    -   CDCl₃: deuterated chloroform    -   conc. concentrated    -   m-CPBA m-chloroperbenzoic acid    -   CLh: hepatic clearance    -   CMV: cytomegalovirus    -   DBB: di-tert-butylbiphenyl    -   DIAD: diisopropyl azodicarboxylate    -   DIG: digoxigenin    -   DIPEA: N,N-diisopropylethylamine    -   DCM: dichloromethylene    -   DAST N,N′-diethylaminosulfur trifluoride    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DMF N,N-dimethylformamide    -   DMF-DMA N,N-dimethylformamide dimethyl acetal    -   DMP Dess-Martin periodinane    -   eq equivalent    -   FDA: Food and Drug Administration    -   PE: petroleum ether    -   DMSO: dimethylsulfoxide    -   DMSO-d6: deuterated dimethylsulfoxide    -   DNA: deoxyribonucleic acid    -   EDTA: ethylenediaminetetraacetic acid    -   EtOH: ethanol    -   EA or EtOAc: ethyl acetate    -   g: gram    -   EC₅₀: half maximal effective concentration    -   HAP: heteroaryldihydropyrimidine    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HBeAb: hepatitis B e antibody    -   HBeAg: hepatitis B e antigen    -   HBsAg: hepatitis B surface antigen    -   HCl: hydrogen chloride    -   HPLC: high performance liquid chromatography    -   HPLC-UV: high performance liquid chromatography with ultraviolet        detector    -   Hz: hertz    -   IPA: isopropanol    -   LiHMDS: lithium hexamethyldisilazide    -   LCMS liquid chromatography—mass spectrometry    -   ESI electrospray ionization    -   obsd. observed    -   TBSCl tert-butyldimethylsilyl chloride    -   NFTh 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane        bis(tetrafluoroborate)    -   TosMIC (p-tolylsulfonyl)methyl isocyanide    -   PhI(OAc)₂ (diacetoxyiodo)benzene    -   METHANOL-d4: deuterated methanol    -   MeOH: methanol    -   mg: milligram    -   MHz: megahertz    -   min: minute    -   mins: minutes    -   mL: milliliter    -   mm: millimeter    -   mM: millimolar    -   mmol: millimole    -   MS: mass spectrometry    -   MsCl: methanesulfonyl chloride    -   MW: molecular weight    -   NaCl: sodium chloride    -   NADP: nicotinamide adenine dinucleotide phosphate (oxidized        form)    -   NADPH: nicotinamide adenine dinucleotide phosphate (reduced        form)    -   Na₂SO₄: sodium sulfate    -   NaOH: sodium hydroxide    -   NBS: N-bromosuccinimide    -   NMR: nuclear magnetic resonance    -   PBS: phosphate buffered saline    -   PD: pharmacodynamics    -   PK: pharmacokinetics    -   prep-HPLC: preparative high performance liquid chromatography    -   Prep-TLC: preparative thin layer chromatography    -   rpm: round per minute    -   sat. saturated    -   SFC: supercritical fluid chromatography    -   SSC: saline-sodium citrate buffer    -   TBAF: tetrabutylammonium fluoride    -   TBAI: tetrabutylammonium iodide    -   TEA: triethylamine    -   Tet: tetracycline    -   TFA: trifluoroacetic acid    -   THF: tetrahydrofuran    -   Tris: tris(hydroxymethyl)aminomethane    -   p-TsCl: p-toluenesulfonyl chloride    -   μg: microgram    -   μL: microliter    -   μM: micromolar    -   UV: ultraviolet detector    -   OD: optical density    -   pgRNA: pre-genomic RNA    -   qPCR: quantitative polymerase chain reaction

General Experimental Conditions

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module. ii) ISCO combi-flash chromatographyinstrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 μM; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using XBridge™ Prep-C18 (5 μm, OBD™ 30×100 mm)column or SunFire™ Prep-C18 (5 μm, OBD™ 30×100 mm) column. Waters AutoPpurification System (Column: XBridge™ Prep-C18, 30×100 mm, SampleManager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solventsystem: acetonitrile and 0.1% ammonium hydroxide in water). For SFCchiral separation, intermediates were separated by chiral column (Daicelchiralpak IC, 5 μm, 30×250 mm) column using Mettler Toledo SFC-MultigramIII system, solvent system: 95% CO₂ and 5% IPA (0.5% TEA in IPA), backpressure 100 bar, detection UV@ 254 nm.

LC/MS spectra of compounds were obtained using a LC/MS (Waters™ Alliance2795-Micromass ZQ), LC/MS conditions were as follows (running time 6mins):

Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid inacetonitrile;

Basic condition: A: 0.1% NH₃.H₂O in H₂O; B: acetonitrile;

Neutral condition: A: H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (MH)⁺.

NMR Spectra were obtained using Bruker Avance 400 MHz.

The microwave assisted reactions were carried out in a Biotage InitiatorSixty microwave synthesizer.

A single crystal was mounted in a loop and cooled to 160 K in a nitrogenstream. Data were collected on a Gemini R Ultra diffractometer (OxfordDiffraction, UK) with Cu—K-alpha-radiation (1.54178 Å) and processedwith the Crysalis-package. Structure solution and refinement wasperformed using the ShelXTL software (Bruker AXS, Karlsruhe).

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

The following examples are intended to illustrate the meaning of thepresent invention but should by no means represent a limitation withinthe meaning of the present invention:

PREPARATIVE EXAMPLES Example 19-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared according to the general synthetic routeshown in Scheme 1. A detailed synthetic route is provided in Scheme 3.

Preparation of Compound A

To a stirred solution of thiazole-2-carbonitrile (1.5 g, 14 mmol) in 5mL of dry MeOH was added dropwise a solution of sodium methoxide (0.74g, 14 mmol) in 10 mL of dry methanol. The reaction mixture was stirredat room temperature until the disappearance of starting materialmonitored by LC/MS. After that, ammonium chloride (1.5 g, 28 mmol) wasadded in one portion and the reaction mixture was stirred overnight. Theundissolved material was removed by filtration and the filtrate wasconcentrated to afford thiazole-2-carboxamidine hydrochloride (CompoundA) as a grey solid which was used directly in the next step withoutfurther purification. MS: calc'd 128 (MH⁺), measured 128 (MH⁺).

Preparation of Compound B

To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g,1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF₃CH₂OH (8 mL) wasadded potassium acetate (0.20 g, 2.0 mmol). The reaction mixture wasrefluxed for 16 hours. After it was cooled to room temperature, thereaction mixture was concentrated and the residue was dissolved in ethylacetate and then washed with brine. The organic layer was dried oversodium sulfate. The solvent was concentrated, and the residue waspurified by column chromatography (ethyl acetate/petroleum ether is from¼ to ½) to afford4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH⁺) 366,measured (MH⁺) 366. ¹H NMR (DMSO-d₆, 400 MHz): 6 ppm 9.98 (s, 1H), 7.97(d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H),7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s,1H), 3.53 (s, 3H), 2.47 (s, 3H).

Preparation of Compound B1

The enantiopure(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B1) was obtained through SFC (SFC-Multigram;IC: 5×250 mm, 5μ) chiral separation of the stereomixture of4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-oxazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B) eluting with a mixed solvent of 85%supercritical CO₂/15% EtOH at 100 mL/min rate. The desired(−)-enantiomer B1 has a relatively short retention time. The absolutestereochemistry of (−)-enantiomer B1 was determined by X-ray diffractionstudy (FIG. 1).

Compound B1: [α]_(D) ²⁰−55.0 (c 0.845, MeOH).

Compound B2: [α]_(D) ²⁰+44.6 (c 0.175, MeOH).

Preparation of Compound C

To a stirred solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (0.37 g, 1.0 mmol) in CCl₄ (5 mL) was added NBS (0.20g, 1.1 mmol) in portions. After the reaction mixture was stirred at roomtemperature for 1 hour, the solvent was removed in vacuo and the residuewas purified by column chromatography to give(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) as a yellow solid. MS: calc'd 445 (MH⁺),measured 445 (MH⁺).

Preparation of Example 1a

To a stirred solution 3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acidmethyl ester (90 mg, 0.48 mmol) (PharmaBlock (Nanjing) R&D Co. Ltd, CAS:1363382-76-6) and(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (104 mg, 0.24 mmol) in C1CH₂CH₂C1 (5 mL) was addedDIPEA (0.15 mL, 0.48 mmol) at room temperature. The reaction mixture wasstirred overnight at room temperature, then diluted with EtOAc (60 mL),washed with sat. NH₄Cl, sat. NaHCO₃ and brine (20 mL) respectively. Theorganic layer was dried over Na₂SO₄, concentrated under reduced pressureto give methyl9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylateas a crude product which was used directly in next step.

Preparation of Example 1

To a stirred solution of methyl9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylatein THF (3 mL) was added 0.3 M aq. LiOH (3 mL) at 0° C. After thereaction mixture was stirred at room temperature for 8 hours, it wasneutralized with 1N HCl to pH around 7, then extracted with EtOAc (60mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄,concentrated under reduced pressure to give the crude product which wasfurther purified by reverse phase HPLC to give Example 1 as a lightyellow solid.

Example 29-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by using 4-methyl-thiazole-2-carbonitrileinstead of thiazole-2-carbonitrile.

Example 39-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid

The title compounds were prepared according to the general syntheticroutes shown in Scheme 2. A detailed synthetic route is provided inScheme 4.

Example 3 was prepared in analogy to Example 1 with the procedure shownin Scheme 3 by using4-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound D) instead of(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B).

Preparation of4-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound D)

Compound D was prepared in analogy to Compound B with the procedureshown in Scheme 3 by using 3,4-difluoro-benzaldehye instead of2-chloro-5-fluorobenzaldehyde.

Example 49-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-bromo-5-fluorobenzaldehydeinstead of 2-chloro-5-fluorobenzaldehyde.

Example 59-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by using 2-bromo-5-fluorobenzaldehydeinstead of 2-chloro-5-fluorobenzaldehyde.

Example 68-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylic acid (Compound F) insteadof 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation 3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylic acid (CompoundF)

Step I: To a solution of6-benzyloxy-3-oxa-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (G7) (160 mg, 0.50 mmol) in MeOH (20 mL) was added Pdon carbon (32 mg). The mixture was stirred at room temperature under H₂for 8 hours, and then filtered. The solvent was removed under reducedpressure. The residue was dissolved in CH₂Cl₂ (10 mL). To the solutionwas added Dess-Martin periodinane (318 mg, 0.75 mmol) at roomtemperature. The reaction mixture was stirred for 4 hours, and thenquenched with sat. NaHCO₃, then extracted with EtOAc (30 mL) threetimes. The combined organic layer was washed successively with sat.Na₂CO₃ (15 mL) three times, sat. NH₄Cl and brine. The organic layer wasdried over Na₂SO₄. The solvent was removed. The residue was purified bycolumn chromatography to give Compound G (100 mg, 88%) as a white solid.MS: calc'd (MH⁺) 228, measured (MH⁺) 228.

Step II: To a solution of methyltriphenylphonium bromide (314 mg, 0.88mmol) in anhydrous THF (5 mL) was added n-BuLi (1.6 M in hexane, 0.58mL) at −10° C. under argon atmosphere. The reaction mixture was warmedto room temperature and then stirred for 2 hours. A solution of CompoundG (100 mg, 0.44 mmol) in anhydrous THF (2 mL) was added to the abovemixture at room temperature. The mixture was stirred for additional 3hours at room temperature, and then quenched with sat. NH₄Cl. Themixture was extracted with EtOAc (30 mL) three times. The combinedorganic layer was washed with sat. NH₄Cl and brine (20 mL) respectively.The organic layer was dried over Na₂SO₄. The solvent was removed underreduced pressure. The residue was purified by column chromatography togive Compound H (80 mg, 81%) as yellowish oil. MS: calc'd (MH⁺) 226,measured (MH⁺) 226.

Step III: To a solution of Compound H (75 mg, 0.33 mmol) in anhydrousTHF was added BH₃/THF (1.0 M solution in THF, 0.43 mL) at 0° C. underargon atmosphere. The reaction mixture was stirred for 1.5 hours at 0°C. To this reaction mixture was added 3N NaOH (0.33 mL, 1.33 mmol) and30% H₂O₂ (0.33 mL) at 0° C. and the mixture was stirred for 1.5 hours at0° C. The reaction mixture was poured into water, and then extractedwith EtOAc (30 mL) three times. The combined organic layer was washedwith sat. NH₄Cl and brine, and then dried over Na₂SO₄. The solvent wasremoved under reduced pressure to give Compound I (80 mg, 98%) ascolorless oil. ¹H NMR (CDCl₃, 400 MHz): 4.15 (m, 1H), 4.04 (m, 1H),3.86-3.96 (m, 3H), 3.76 (m, 2H), 3.57 (d, J=9.8 Hz, 1H), 2.55 (m, 1H),2.20 (m, 1H), 1.50 (s, 9H).

Step IV: To a solution of Compound I (80 mg, 0.33 mmol) in CH₂Cl₂ (10mL) was added Dess-Martin periodinane (210 mg, 0.50 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 2hours, and then diluted with EtOAc (60 mL). The reaction mixture waswashed successively with sat. Na₂CO₃ (10 mL) three times, sat. NH₄Cl (20mL) and brine (20 mL). The organic layer was dried over Na₂SO₄. Thesolvent was removed under reduced pressure to give Compound J (80 mg,99%) as colorless oil. ¹H NMR (CDCl₃, 400 MHz): 9.93 (d, J=1.8 Hz, 1H),4.38 (m, 1H), 4.24 (m, 1H), 3.76 (m, 2H), 3.66 (m, 2H), 3.01 (m, 1H),2.33 (m, 1H), 2.26 (m, 1H), 1.48 (s, 9H).

Step V: To a solution of Compound J (80 mg, 0.33 mmol) in t-BuOH (3 mL)was added a-methyl-2-butene (0.75 mL) and a solution of NaClO₂ (278 mg,3.07 mmol) and NaH₂PO₄/2H₂O (373 mg, 2.39 mmol) in H₂O (3 mL) at roomtemperature. The reaction mixture was stirred for 2 hours at roomtemperature. t-BuOH was removed under reduced pressure and aqueousresidue was poured into 10% aqueous solution of citric acid. The mixturewas extracted with EtOAc (30 mL) three times. The combined organic layerwas washed with sat. NH₄Cl and brine, and then dried over Na₂SO₄. Thesolvent was removed under reduced pressure. The residue was furtherdried under reduced pressure to give Compound K (80 mg, 94%) ascolorless oil. ¹H NMR (CDCl₃, 400 MHz): 9.63 (brs, 1H), 4.32 (m, 1H),4.18 (m, 1H), 4.05 (d, J=10.8 Hz, 1H), 3.68 (m, 2H), 3.64 (d, J=10.8 Hz,1H), 3.26 (m, 1H), 2.43 (dd, J=12.8, 5.5 Hz, 1H), 2.27 (m, 1H), 1.50 (s,9H).

Step VI: To a solution of Compound K (80 mg, 0.31 mmol) in CH₂Cl₂ (5 mL)was added trifluoroacetic acid (2 mL) at 0° C. The mixture was stirredat room temperature for 2 hours. The solvent was removed under reducedpressure. The residue was further dried under high-vacuum to give3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylic acid (Compound F) (85 mg,100%) as brown oil. MS (ESI, [M+H]⁺): Calc'd. for C₇H₁₂NO₃: 158. Found:158.

Preparation of Literature Known Intermediate G7 (J. Org. Chem. 2010, 75,1643)

Step I: A 1.6 M solution of n-butyllithium in hexanes (46.5 ml, 75 mmol)was added to a solution of 2,2,6,6-tetramethylpiperidine (12.6 mL, 75mmol) in THF (100 mL) at −78° C. under argon. N-Boc-pyrrole (5 g, 30mmol) in THF (25 mL) was then added to the mixture. The mixture wasstirred for 3 hours, then transferred into methyl chloroformate (3equivalents, 6.95 mL) via cannula and stirred for a further 30 minutes.Sat. NH₄Cl (20 mL) was added and the mixture was allowed to warm to roomtemperature. The mixture was then diluted with ether (50 mL), washedwith 1 M HCl solution (100 mL) and sat. brine (100 mL). The organiclayers were dried over Na₂SO₄, filtered and concentrated to give thecrude product which was purified by flash column chromatography to give1-tert-butyl, 2,5-dimethyl pyrrole-1,2,5-tricarboxylate (6.60 g, 78%) asa white solid.

Step II: To a Schlenk tube containing DBB (15 mg, 0.10 mmol) andantibumping granules under argon was added freshly cut lithium wire (98mg, 14 mmol). The contents of the tube were then stirred until thelithium had been completely reduced to a powder. The tube was thencooled to −78° C. and THF (25 mL) was added resulting in a turquoisesolution. 1-tert-butyl, 2,5-dimethyl pyrrole-1,2,5-tricarboxylate (1.0g, 3.5 mmol) was then added in THF (10 mL) and the resulting redsolution was stirred at −78° C. until the solution appeared turquoiseagain. 1,2-Dibromoethane (0.2 mL, 7.0 mmol) was then added, followed by2,6-ditertbutylphenol (1.5 g, 7.0 mmol) in THF (10 mL). The mixture wasthen stirred for a further 2.5 hours before the addition of Sat. NH₄Clsolution (10 mL) and the mixture was warmed to room temperature. Themixture was extracted with ether (2×20 mL) and the organic layers werecombined, then dried over Na₂SO₄, filtered and concentrated to give thecrude product which was purified by flash chromatography to give1-tert-butyl, 2,5-dimethyl(2S,5R)-2,5-dihydropyrrole-1,2,5-tricarboxylate (800 mg, 80%) as yellowoil.

Step III: To a solution of 1-tert-butyl, 2,5-dimethyl(2S,5R)-2,5-dihydropyrrole-1,2,5-tricarboxylate (6.6 g, 23.1 mmol) inTHF (100 mL) was added slowly a LiBH₄ solution (2 M in THF, 34.7 mL,69.4 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 3 hours and then cooled to 0° C. HCl solution (1 M, 30mL) was added to the reaction mixture and the reaction was stirred for10 minutes before being diluted with EtOAc. The organic layer wasseparated, and the aqueous phase was extracted with EtOAc. Combinedorganic phases were washed with water and brine and dried over Na₂SO₄.The organic solvent was removed to give the crude product, which waspurified by flash chromatography on silica gel to give tert-butyl(2R,5S)-2,5-bis(hydroxymethyl)-2,5-dihydropyrrole-1-carboxylate (3.8 g,72%). ¹H NMR (CDCl₃, 300 MHz): 5.77 (d, 2H, J=3.0 Hz), 4.70 (s, 1H),4.59 (s, 1H), 4.06 (d, 1H, J=11.3 Hz), 3.97 (d, 1H, J=11.3 Hz), 3.66 (m,2H), 1.49 (s, 9H).

Step IV: To a solution of tert-butyl(2R,5S)-2,5-bis(hydroxymethyl)-2,5-dihydropyrrole-1-carboxylate (3.57 g,15.6 mmol) in DMF (15 mL) were added TBSCl (5.16 g, 34.3 mmol) andimidazole (3.18 g, 46.7 mmol). The mixture was heated at 80° C. for 30minutes, then cooled to room temperature. The mixture was taken up inwater (50 mL) and EtOAc (50 mL). The organic layer was separated, andthe aqueous phase was extracted with EtOAc. The combined organic phaseswere washed with water and brine and dried over Na₂SO₄. The organicsolvent was removed to give the crude product, which was purified byflash chromatography on silica gel to give the tert-butyl(2R,5S)-2,5-diethyl-2,5-dihydropyrrole-1-carboxylate (7.12 g, 98%). ¹HNMR (CDCl₃, 300 MHz): 5.85 (d, 2H, J=3.0 Hz), 4.50 (s, 1H), 4.36 (s,1H), 3.85 (m, 2H), 3.47 (t, 1H, J=8.0 Hz), 3.35 (t, 1H, J=8.7 Hz), 1.43(s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.00 (s, 12H).

Step V: To a solution of tert-butyl(2R,5S)-2,5-diethyl-2,5-dihydropyrrole-1-carboxylate (4.8 g, 10.5 mmol)in THF (50 mL) was added slowly BH₃.DMS solution (2M in THF, 6.97 mL,13.9 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 3 hours and then cooled to 0° C. NaOH solution (5 M,12.6 mL, 63.2 mmol) was added to the reaction mixture, followed byaddition of H₂O₂ (30%, 6.33 mL, 62.0 mmol). The resulting mixture wasstirred for 5 hours before diluted with EtOAc. The organic layer wasseparated, and the aqueous phase was extracted with EtOAc. The combinedorganic phases were washed with water and brine and dried over Na₂SO₄.The organic solvent was removed to give the crude product, which waspurified by flash chromatography on silica gel to give the tert-butyl(2R,5S)-2,5-diethyl-3-hydroxy-pyrrolidine-1-carboxylate (3.8 g, 77%).¹HNMR(CDCl₃, 300 MHz): 4.35 (s, 1H), 4.0-3.46 (m, 5H), 3.33 (m, 1H),2.22-2.10 (m, 1H), 1.89-1.73 (m, 1H), 1.39 (s, 9H), 0.82 (s, 18H), −0.01(s, 6H), −0.03 (s, 6H).

Step VI: To a solution of tert-butyl(2R,5S)-2,5-diethyl-3-hydroxy-pyrrolidine-1-carboxylate (2.51 g, 5.3mmol) in THF (50 mL) was added NaH (60%, 0.423 g, 10.6 mmol). Themixture was stirred at room temperature for 30 minutes, and benzylbromide (1.085 g, 6.3 mmol) and TBAI (0.195 g, 0.5 mmol) were added. Themixture was stirred at room temperature for 12 hours and quenched byaddition of sat. NH₄Cl (20 mL). The mixture was concentrated and theresidue was taken up in water and EtOAc. The organic layer wasseparated, and the aqueous phase was extracted with EtOAc. The combinedorganic phases were washed with water and brine and dried over Na₂SO₄.The organic solvent was removed to give the crude product, which waspurified by flash chromatography on silica gel with give the 3-OBnintermediate (2.9 g, 95%) as colorless oil. To a solution of the 3-OBnintermediate (2.9 g, 5.2 mmol) in THF (50 mL) was added slowly of TBAFsolution (1M in THF, 21.8 mL, 21.8 mmol) at 0° C. The resulting mixturewas stirred at room temperature for 6 hours and quenched by addition ofsat. NH₄Cl (10 mL). The mixture was concentrated in vacuo, and theresidue was treated with water and EtOAc. The organic layer wasseparated, and the aqueous phase was extracted with EtOAc. The combinedorganic phases were washed with water and brine and dried over Na₂SO₄.The organic solvent was removed in vacuo to give the crude product,which was purified by flash chromatography on silica gel to givetert-butyl(2R,5R)-3-benzyloxy-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate(1.15 g, 63%). ¹H NMR (DMSO-d⁶, 300 MHz): 7.31 (m, 5H), 4.82 (t, 1H,J=5.5 Hz), 4.71 (s, 1H), 4.47 (m, 2H), 4.02 (s, 1H), 3.89-3.73 (m, 2H),3.54-3.40 (m, 3H), 3.22 (m, 1H), 2.04 (m, 2H), 1.39 (s, 9H).

Step VII: To a solution of tert-butyl(2R,5R)-3-benzyloxy-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate(1.15 g, 3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2mmol). The mixture was stirred at room temperature for 30 minutes andcooled to 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL)was slowly added to the mixture. The reaction mixture was then stirredat room temperature for 12 hours and quenched by sat. NH₄Cl solution (20mL). The mixture was concentrated in vacuo, and the residue was taken upwith water and EtOAc. The organic layer was separated, and the aqueousphase was extracted with EtOAc. The combined organic phases were washedwith water and brine and dried over Na₂SO₄. The organic solvent wasremoved in vacuo to give the crude product, which was purified by flashchromatography on silica gel to give6-benzyloxy-3-oxa-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (716 mg, 66%) as an off-white solid. ¹H NMR (CDCl₃, 300MHz): 7.35-7.27 (m, 5H), 4.59-4.43 (m, 2H), 4.38-4.07 (m, 3H), 3.73-3.56(m, 3H), 3.47 (t, 1H, J=9.8 Hz), 2.27 (m, 1H), 1.96 (m, 1H), 1.48 (s,4.5H), 1.44 (s, 4.5H).

Example 7(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound L) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound L)

To a stirred solution of7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butylester (100 mg, 0.41 mmol) in MeOH (5 mL) was added NaBH₄ (47 mg, 1.24mmol) in one portion at room temperature. The mixture was stirred atroom temperature overnight, and then quenched with sat. NaHCO₃. Themixture was extracted with EtOAc (20 mL) three times. The organic layerwas washed with sat. NaHCO₃ and brine (20 mL) respectively. The organiclayer was dried over Na₂SO₄, and then filtered. The solvent wasconcentrated under reduced pressure to give a crude product La, whichwas dissolved in CH₂Cl₂ (5 mL). Trifluoroacetic acid (2 mL) was added tothe solution dropwise at 0° C. After being stirred at room temperaturefor 2 hours, the mixture was concentrated under reduced pressure. Theresidue was further dried on high-vacuum to give3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound L) which was directlyused for next step. MS: calc'd (MH⁺) 144, measured (MH⁺) 144.

Example 8(R)-6-(7-Acetoxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using acetic acid3-oxa-9-aza-bicyclo[3.3.1]non-7-yl ester (Compound M) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of acetic acid 3-oxa-9-aza-bicyclo[3.3.1]non-7-yl ester(Compound M)

Step I: To a solution of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one(PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1126795-00-3) (1.0 g, 5.6 mmol)and DIPEA (2.9 mL, 17.7 mmol) in CH₂Cl₂ (30 mL) was added CbzCl (0.76mL, 5.3 mmol) at 0° C. under argon atmosphere. The mixture was stirredat room temperature for 2 hours, and then quenched with sat. NH₄Cl, thenextracted with EtOAc (50 mL) three times. The combined organic layer waswashed with 1N aq. HCl, sat. NaHCO₃ and brine respectively. The organiclayer was dried over Na₂SO₄. The solvent was removed under reducedpressure to give Compound N (1.4 g, 91%).

Step II: To a solution of Compound N (810 mg, 2.9 mmol) in THF (20 mL)was added NaBH₄ (220 mg, 5.8 mmol). The reaction mixture was stirred atroom temperature for 3 hours, and then quenched with sat. NH₄Cl. THF wasremoved under reduced pressure and the residue was extracted with EtOAc(30 mL) three times. The combined organic layer was washed with sat.NH₄Cl, sat. NaHCO₃ and brine respectively, and then dried over Na₂SO₄.The solvent was concentrated to give Compound 0 (700 mg, 87%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): 7.39-7.32 (m, 5H), 5.45 (d, 1H), 5.15(s, 2H), 4.21-4.11 (m, 2H), 3.89-3.72 (m, 4H), 2.23-2.12 (m, 2H),1.87-1.82 (m, 2H).

Step III: To a solution of Compound 0 (300 mg, 1.1 mmol), 4-nitrobenzoicacid (181 mg, 1.1 mmol) and PPh₃ (578 mg, 2.2 mmol) in anhydrous THF(5.0 mL) was added DIAD (445 mg, 2.2 mmol) under argon. The reactionmixture was stirred at room temperature for 16 hours. The solvent wasremoved and the residue was purified by Prep-TLC (DCM/MeOH=30/1) to giveCompound P (230 mg, 50%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): 8.28(d, 2H), 8.17 (d, 2H), 7.38-7.31 (m, 5H), 6.22-6.17 (m, 1H), 5.19 (s,2H), 4.33 (s, 1H), 4.25 (s, 1H), 3.93-3.85 (m, 2H), 3.74-3.70 (m, 2H),2.34-2.29 (m, 2H), 1.98-1.88 (m, 2H).

Step IV: To a solution of Compound P (230 mg, 0.54 mmol) in THF (3 mL)was added aq. LiOH (1.0 M, 3.0 mL). The reaction mixture was stirred atroom temperature for 2 hours, and then diluted with EtOAc (80 mL). Theorganic layer was washed successively with sat. Na₂CO₃ (10 mL) threetimes sat. NH₄Cl (20 mL) and brine (20 mL). The organic layer was driedover Na₂SO₄, and then concentrated to give Compound Q (89 mg, 60%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): 7.40-7.31 (m, 5H), 5.16 (s, 2H),4.91-4.86 (m, 1H), 4.23 (s, 1H), 4.16 (s, 1H), 3.83-3.65 (m, 4H),2.15-2.09 (m, 2H), 1.74-1.69 (m, 2H).

Step V: The crude Compound Q was dissolved in HBr/HOAc (33 wt. %, 3 mL).The mixture was stirred at room temperature for 2 hours. The solvent wasremoved under reduced pressure and further dried on high-vacuum to give3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound R) and3-oxa-9-aza-bicyclo[3.3.1]non-7-yl ester (Compound M) which weredirectly used for next step.

Compound R: MS: calc'd (MH⁺) 144, measured (MH⁺) 144.

Compound M: MS: calc'd (MH⁺) 186, measured (MH⁺) 186.

Example 9(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound R) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 10(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound S)instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Preparation of 7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol(Compound S)

Step I: To a stirred solution of 3-oxa-9-azabicyclo[3.3.1]nonan-7-onehydrochloride (1.26 g, 7.08 mmol, cas:1126795-00-3, purchased fromPharmaBlock (Nanjing) R&D Co. Ltd,) and potassium carbonate (2.94 g,14.16 mmol) in DMF (10 mL) was added benzyl bromide (1.33 g, 7.78 mmol)dropwise at room temperature. The resulting mixture was stirred at roomtemperature overnight, then concentrated and the residue was partitionedbetween H₂O (5 mL) and EtOAc (20 mL). The organic layer was dried, andthen concentrated. The residue was purified to give Compound T (1.38 g,84.2%). ¹H NMR (CDCl₃, 400 MHz): 7.36 (m, 5H), 3.93 (s, 2H), 3.86 (d,J=11.0, 2H), 3.73 (d, J=10.8, 2H), 3.18 (d, J=5.6, 2H), 2.76 (dd,J=15.9, 5.6 Hz, 2H), 2.35 (d, J=15.6, 2H) ppm. LC/MS: calc'd 232 (MH⁺),exp 232 (MH⁺).

Step II: A mixture of potassium tert-butoxide (0.292 g, 2.60 mmol) andmethyltriphenyl phosphonium bromide (0.927 g, 2.60 mmol) in dry THF (5mL) was stirred at 0° C. for 30 mins. Then a solution of9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (Compound T) (0.231 g,1.00 mmol) in dry THF (2 mL) was added to the reaction mixture. Theresulting mixture was allowed to warm to room temperature and thenheated at 50° C. overnight. The mixture was concentrated and the residuewas partitioned between H₂O (2 mL) and EtOAc (10 mL). The organic phasewas dried, and then concentrated. The residue was purified to giveCompound U (0.098 g, 42.8%). ¹H NMR (CDCl₃, 400 MHz): 7.37 (m, 5H), 4.73(s, 2H), 3.98 (m, 4H), 3.79 (d, J=10.8, 2H), 2.83 (m, 4H), 2.29 (m, 2H).LC/MS: calc'd 230 (MH⁺), exp 230 (MH⁺).

Step III: To a stirred solution of9-benzyl-7-methylene-3-oxa-9-azabicyclo[3.3.1]nonane (Compound U) (0.070g, 0.30 mmol) in acetone (2 mL) and H₂O (0.5 mL) was addedN-methylmorpholine-N-oxide (0.140 mg, 0.9 mmol) and osmium tetroxide(0.05 ml, 4% in water, 0.01 mmol) at room temperature. The mixture wasstirred at room temperature overnight. The mixture was quenched withsaturated Na₂S₂O₃ (10 mL) and then extracted with EtOAc (20 ml×2). Theorganic layer was dried, and then concentrated. The residue was purifiedto give Compound V (0.070 g, 88.7%). LC/MS: calc'd 264 (MH⁺), exp 264(MH⁺).

Step IV: A mixture of9-benzyl-7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (CompoundV) (0.080 g, 0.30 mmol) and Pd/C (20 mg) in MeOH (2 mL) was stirredunder H₂ at room temperature overnight. The mixture was filtered and thefiltrate was concentrated to give Compound S (0.040 g, 77.0%). LC/MS:calc'd 174 (MH⁺), exp 174 (MH⁺).

Example 11(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound W)instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Preparation of 7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane(Compound W)

To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acidtert-butyl ester (WuXi AppTec (Wuhan) Co., Ltd, CAS: 864448-41-9) (173mg, 0.76 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added DIPEA (195 mg, 1.52mmol) and CbzCl (155 mg, 0.91 mmol). The reaction mixture was warmed upto room temperature and then stirred for 2 hours. The mixture wasquenched with sat. NH₄Cl, and then extracted with EtOAc (60 mL). Theorganic layer was washed with sat. NH₄Cl, sat. NaHCO₃ and brine (20 mL)respectively, and then dried over Na₂SO₄. The solvent was removed togive a white solid (250 mg, 78%), which was dissolved in CH₂Cl₂ (2 mL).To the solution was added HCl in dioxane (4 M, 2 mL). The reactionmixture was stirred at room temperature for 2 hours. The solvent wasremoved to give 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound X) (205 mg, 100%) as a white solid. MS: calc'd(MH⁺) 263, measured (MH⁺) 263.

To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound X) (100 mg, 0.33 mmol) in CH₂Cl₂ (5 mL) was addedDIPEA (0.23 mL, 1.32 mmol) and methanesulfonyl chloride (57 mg, 0.49mol). The reaction mixture was stirred at room temperature for 1 hour,and then quenched with sat. NH₄Cl, then diluted with EtOAc (60 mL). Themixture was washed with sat. NH₄Cl, sat. NaHCO₃ and brine (20 mL)respectively. The organic layer was dried over Na₂SO₄. The solvent wasremoved under reduced pressure to give7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound Y) (105 mg, 95%) as yellowish oil. MS: calc'd(MH⁺) 341, measured (MH⁺) 341.

To a solution of the crude Compound Y in MeOH (20 mL) was added 10% Pdon carbon (20 mg). The mixture was stirred under one atmosphere pressureof hydrogen at room temperature. After the reaction was completed, themixture was filtered and concentrated to give7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound W) (50mg, 78%) which was directly used for next step. MS: calc'd (MH⁺) 207,measured (MH⁺) 207.

Example 12(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound Z) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of 7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CompoundZ)

To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound X) (84 mg, 0.28 mmol) in MeOH (5 mL) was addedparaformaldehyde (41 mg, 1.38 mmol) and NaBH₄ (21 mg, 0.56 mmol). Thereaction mixture was refluxed for 16 hours under argon atmosphere, andthen quenched with sat. NaHCO₃, then extracted with EtOAc (20 mL) threetimes. The combined organic layer was washed successively with sat.NH₄Cl, NaHCO₃ and brine, and then dried over Na₂SO₄. The solvent wasconcentrated under reduced pressure. The residue was dissolved in MeOH(20 mL). To the solution was added 10% Pd on carbon (20 mg). The mixturewas stirred under one atmosphere pressure of hydrogen at roomtemperature. After the reaction was completed, the mixture was filteredand concentrated to give the crude7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound Z) (32 mg, 81%)which was directly used for next step. MS: calc'd (MH⁺) 143, measured(MH⁺) 143.

Example 13(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound AA) insteadof 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of 7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane(Compound AA)

To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound X) (100 mg, 0.33 mmol) in DMF (5 mL) was addedK₂CO₃ (91 mg, 0.66 mmol) and 2-iodopropane (111 mg, 0.66 mmol). Thereaction mixture was heated to 80° C. and stirred for 16 hours. Themixture was diluted with EtOAc (60 mL), and then washed with sat. NH₄Cl,sat. NaHCO₃ and brine (20 mL) respectively. The organic layer was driedover Na₂SO₄, and then concentrated to give the crude product which wasdissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon(20 mg). The mixture was stirred under one atmosphere pressure of H₂ atroom temperature. After the reaction was completed, the mixture wasfiltered and concentrated to give the crude7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound AA) (32 mg,57%) which was directly used for next step. MS: calc'd (MH⁺) 171,measured (MH⁺) 171.

Example 14(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CompoundAB) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Preparation of7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CompoundAB)

To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidbenzyl ester (Compound X) (100 mg, 0.33 mmol) in DMF (5 mL) was addedK₂CO₃ (91 mg, 0.66 mmol) and 2-iodopropane (95 mg, 0.76 mmol). Thereaction mixture was heated to 80° C. and stirred for 16 hours. Themixture was diluted with EtOAc (60 mL), and then washed with sat. NH₄Cl,sat. NaHCO₃ and brine (20 mL) respectively. The organic layer was driedover Na₂SO₄, and then concentrated to give the crude product which wasdissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon(20 mg). The mixture was stirred under hydrogen atmosphere at roomtemperature. After the reaction was completed, the mixture was filteredand concentrated to give the crude7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CompoundAB) (51 mg, 81%) which was directly used for next step. MS: calc'd (MH⁺)193, measured (MH⁺) 193.

Example 15(R)-6-(7-Acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below (Scheme 5).

To a solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC) (50 mg, 0.1 mmol) and triethylamine(0.042 mL, 0.3 mmol) in CH₂Cl₂ (5 mL) was added acetyl chloride (16 mg,0.2 mmol) dropwise at ice-bath. The mixture was stirred at 0° C. for 2hours. The mixture was concentrated in vacuo. The residue was extractedwith ethyl acetate (20 mL×2) and then washed with saturated aqueoussodium bicarbonate solution (20 mL×2). The organic layer was dried overanhydrous sodium sulfate and then concentrated in vacuo. The residue waspurified by prep-HPLC to afford(R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Example 15) as a light yellow solid (45 mg).

Preparation of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC)

To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acidtert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) inCH₂Cl₂ (10 mL) was added(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated in vacuo. Theresidue was purified by flash column chromatography to afford9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylicacid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH⁺) 592,measured (MH⁺) 592.

To a solution of9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylicacid tert-butyl ester (280 mg, 0.47 mmol) in CH₂Cl₂ (10 mL) was addedTFA (2 mL) dropwise in ice-bath. The mixture was stirred at roomtemperature for 16 hours. The mixture was neutralized with a saturatedaqueous sodium bicarbonate solution and then extracted with CH₂Cl₂ (20mL×2). The organic layer was washed with saturated aqueous sodiumbicarbonate solution (20 mL×2), and then dried over anhydrous sodiumsulfate and then concentrated in vacuo to afford(R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC) as light yellow oil (230 mg, 98%) whichwas used for next step without further purification. MS: calc'd (MH⁺)492, measured (MH⁺) 492.

Example 16(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methylsulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below.

To a solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC) (50 mg, 0.1 mmol) and triethylamine(0.042 mL, 0.3 mmol) in CH₂Cl₂ (5 mL) was added methylsulfamoyl chloride(26 mg, 0.2 mmol) dropwise in ice-bath. The mixture was stirred at 0° C.for 2 hours. The mixture was concentrated in vacuo. The residue wasextracted with ethyl acetate (20 mL×2). The organic layer was washedwith saturated aqueous sodium bicarbonate solution (20 mL×2), and thendried over anhydrous sodium sulfate and then concentrated in vacuo. Theresidue was purified by preparative HPLC to afford Example 16 as a lightyellow solid (35 mg)

Example 179-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below.

To a solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (compound AC) (50 mg, 0.1 mmol) and triethylamine(0.042 mL, 0.3 mmol) in CH₂Cl₂ (5 mL) was added methyl chloroformate (19mg, 0.2 mmol) dropwise in ice-bath. The mixture was stirred at 0° C. for3 hours. The mixture was concentrated in vacuo. The residue wasextracted with ethyl acetate (20 mL×2). The organic layer was washedwith saturated aqueous sodium bicarbonate solution (20 mL×2), and thendried over anhydrous sodium sulfate and then concentrated in vacuo. Theresidue was purified by preparative HPLC to afford Example 17 as a lightyellow solid (19 mg).

Example 18(R)-6-(7-Carbamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below.

To a solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC) (60 mg, 0.12 mmol) and triethylamine(0.17 mL, 1.2 mmol) in CH₂Cl₂ (5 mL) was added trimethylsilanylisocyanate (55 mg, 0.48 mmol) dropwise in ice-bath. The mixture wasstirred at 0° C. for 16 hours. The mixture was concentrated in vacuo.The residue was purified by preparative HPLC to afford Example 18 as alight yellow solid (19 mg).

Example 19(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-sulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below.

To a solution of Compound AD in CH₂Cl₂ (5 mL) was added TFA (0.5 mL)dropwise in ice-bath. The mixture was stirred at room temperature for 2hours. The mixture was neutralized with a saturated aqueous sodiumbicarbonate solution and then extracted with CH₂Cl₂ (20 mL×2). Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution (20 mL×2), and then dried over anhydrous sodium sulfate andthen concentrated in vacuo. The residue was purified by preparative HPLCto afford Example 19 as a light yellow solid (18 mg).

Preparation of Compound AD

To a solution of chlorosulfonyl isocyanate (0.087 mL, 1 mmol) in CH₂Cl₂(20 mL) was added tert-butanol (0.096 mL, 1 mmol) in ice-bath. Themixture was stirred at room temperature for 2 hours. A solution ofN-tert-butoxycarbonylsulfamoyl chloride in CH₂Cl₂ (−0.05 M) wasobtained, which was used for next step without further purification.

To a solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (60 mg, 0.12 mmol) and triethylamine (0.05 mL, 0.36mmol) in CH₂Cl₂ (10 mL) was added N-tert-butoxycarbonylsulfamoylchloride in dichloromethane (0.05 M, 2.5 mL, 0.125 mmol) dropwise inice-bath. The mixture was stirred at 0° C. for 1 hour. The mixture wasconcentrated in vacuo. The residue was purified by flash columnchromatography to afford compound AD as a brown solid (80 mg, 99%). MS:calc'd (MH⁺) 671, measured (MH⁺) 671.

Example 20(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(1-ethoxycarbonyl-1-methyl-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using2-methyl-2-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-7-yl)-propionic acid ethylester (Compound AE) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of2-methyl-2-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-7-yl)-propionic acid ethylester (Compound AE)

A mixture of7-(1-ethoxycarbonyl-1-methyl-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (Compound X) (130 mg, 0.50 mmol), cesium carbonate(489 mg, 1.5 mmol) and 2-bromo-2-methyl-propionic acid ethyl ester (0.15mL, 1.0 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for5 hours. The mixture was then filtered and washed with ethyl acetate (20mL×2). The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography to afford7-(1-ethoxycarbonyl-1-methyl-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (Compound AF) as brown oil (0.090 g, 47%). MS: calc'd(MH⁺) 377, measured (MH⁺) 377.

A mixture of2-methyl-2-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-7-yl)-propionic acid ethylester (Compound AF) (90 mg, 0.24 mmol) and 10% palladium on activatedcarbon (20 mg) in methanol (20 mL) was stirred at room temperature underhydrogen pressure (30 psi) for 16 hours. The catalyst was filtered offand the filtrate was concentrate in vacuo to afford2-methyl-2-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-7-yl)-propionic acid ethylester (Compound AE) as light yellow oil (55 mg, 95%) which was useddirectly in the coupling reaction without further purification. MS:calc'd (MH⁺) 242, measured (MH⁺) 242.

Example 21

(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2-hydroxy-acetyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Preparation of Example 21

A mixture of(R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AC) (61.4 mg, 0.125 mmol), glycolic acid (20mg, 0.25 mmol), EDCI (48 mg, 0.25 mmol) and triethylamine (0.09 mL,0.625 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature for 16hours. The mixture was concentrated in vacuo. The residue was purifiedby preparative HPLC to afford Example 21 as a light yellow solid (10mg).

Example 227-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(WuXi AppTec (Wuhan) Co., Ltd, CAS: 478647-20-0) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 23(S)-2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-5,5-difluoro-2-aza-bicyclo[2.2.2]octane-3-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using(S)-6,6-difluoro-2-aza-bicyclo[2.2.2]octane-3-carboxylic acid (WuXiAppTec (Wuhan) Co., Ltd, CAS: 1394117-03-3) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 24(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock (Nanjing)R&D Co. Ltd, CAS: 1389441-75-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 25(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (compoundAG) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Preparation of Compound AG

To a solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (200mg, 0.9 mmol) in 10 mL of methanol was added dropwise sulfuryl chloride(0.3 mL, 1.8 mmol) under ice cooling. After the mixture was refluxed for3 hours, it was concentrated in vacuo. The residue was extracted withethyl acetate (20 mL×2). The organic layer was washed with saturatedaqueous sodium bicarbonate solution (20 mL×2), and then dried overanhydrous sodium sulfate and then concentrated in vacuo to afford(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (CompoundAG) as colorless oil (179 mg, 99%) which was used directly in next stepwithout further purification. MS: calc'd (MH⁺) 200, measured (MH⁺) 200.

Example 26(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate instead ofmethyl acetoacetate and (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid(PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1389441-75-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 276-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 3 with theprocedure shown in Scheme 4 by using(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock (Nanjing)R&D Co. Ltd, CAS: 1389441-75-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 28(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(7-carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-bromo-5-fluorobenzaldehydeinstead of 2-chloro-5-fluorobenzaldehyde and(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock (Nanjing)R&D Co. Ltd, CAS: 1389441-75-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 29(S)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 3,4-diflurobenzaldehyde instead of2-chloro-5-fluorobenzaldehyde, ethyl acetoacetate and(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock (Nanjing)R&D Co. Ltd, CAS: 1389441-75-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 30(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by usinghydroxy-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester(Compound AH) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester.

Preparation of hydroxy-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acidmethyl ester (Compound AH)

Step I: To a stirred solution of(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (CompoundAG) (179 mg, 0.90 mmol) in 10 mL of dichloromethane was addedtriethylamine (0.5 mL, 3.6 mmol). The mixture was stirred at roomtemperature for 15 mins and then benzyl chloroformate (0.25 mL, 1.8mmol) was added dropwise at 0° C. After the reaction mixture was stirredat room temperature for 2 hours, it was concentrated in vacuo. Theresidue was purified by flash column chromatography to afford7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester as colorless oil (Compound AI) (0.13 g, 44%) MS:calc'd (MH⁺) 334, measured (MH⁺) 334.

Step II: To a stirred solution of7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (Compound AI) (130 mg, 0.39 mmol) in anhydrous THF at−78° C. was added 1 M NaN(trimethylsilyl)₂ in THF (0.43 mL, 0.43 mmol)during a period of 5 mins. Then the mixture was stirred for 20 mins at−78° C. To this solution was added a pre-cooled (−78° C.) solution of2-(phenylsulfonyl)-3-phenyloxaziridine (153 mg, 0.585 mmol) in THF. Thesolution was stirred for 30 mins at −78° C. and then quenched by rapidaddition of 6N HCl. The mixture was stirred at room temperature for 30mins and then diluted with dichloromethane. The mixture was washed withwater and 5% aqueous sodium bicarbonate. The organic layer was driedover anhydrous sodium sulfate and then concentrated in vacuo. Theresidue was purified by flash column chromatography to afford7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (Compound AJ) (0.30 g, 85%). MS: calc'd (MH⁺) 350,measured (MH⁺) 350.

Step III: A mixture of7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (Compound AJ) (300 mg, 0.86 mmol) and 10% palladium onactive carbon (100 mg) in methanol (10 mL) was stirred at roomtemperature under hydrogen (30 psi) for 16 hours. The catalyst wasfiltered off. The filtrate was concentrate in vacuo to affordhydroxy-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester(Compound AH) (107 mg, 57%) which was used for the next step withoutfurther purification. MS: calc'd (MH⁺) 216, measured (MH⁺) 216.

Example 31(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylicacid tert-butyl ester (WuXi AppTec (Wuhan) Co., Ltd, CAS: 1311183-41-1)instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Example 32(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6]dodeca-2(6),3-diene(Compound AK) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester.

Preparation of3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene(Compound AK)

Step I: To a solution of7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butylester (482 mg, 2 mmol) in THF (5 mL) was added LiHMDS (3 mL, 3 mmol)slowly at −78° C. After 15 mins, 1-pyrazol-1-yl-ethanone (264 mg, 2.4mmol) was added, and the resulting mixture was stirred at −78° C. for 1hour and then at room temperature for 1 hour. The reaction mixture wasquenched with water, and then extracted with EA (20 mL×2). The organiclayer was concentrated in vacuo. The residue was purified by flashchromatography (EA in PE 0%˜70%) to afford6-acetyl-7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acidtert-butyl ester (compound AL) as light yellow oil (56 mg, 20%). LC/MS:calc'd 284 (MH⁺), exp 284 (MH⁺).

Step II: To a solution of Compound AL (56 mg, 0.2 mmol) in EtOH (4 mL)was added hydrazine monohydrate (50 mg, 1.0 mmol), then the reactionmixture was sealed and heated at 80° C. for 2 hours. The reactionmixture was concentrated in vacuo. The residue was dissolved in DCM/TFA(3 mL, 2:1) and then stirred at room temperature for 2 hours. Thesolvent was removed and the residue was dried under vacuum to afford3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6]dodeca-2(6),3-diene(Compound AK) as yellow foam (crude 50 mg, 100%). LC/MS: calc'd 184(MH⁺), exp 184 (MH⁺).

Example 33(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5-methyl-3-oxo-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6]dodec-2(6)-en-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using5-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6]dodec-2(6)-en-3-one(Compound AM) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester.

Preparation of5-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6)-en-3-one(Compound AM)

Step I: To a suspension of t-BuOK (1.82 g, 16.26 mmol) in toluene (30mL) was added dimethyl carbonate (0.98 g, 10.84 mmol). The mixture washeated at 90° C. for 5 mins, and then7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butylester (1.3 g, 5.4 mmol) was added. After the resulting mixture wasstirred at 90° C. for 30 mins, the mixture was turned to brown gel, andthen DMF (1.5 mL) was added to get a brown solution. The mixture wasstirred at 90° C. for 3 hours. After it was cooled to room temperature,silica gel (25 g, 100200 mesh) was added and the solvent wasconcentrated in vacuo. The residue was purified by flash columnchromatography (EtOAc in PE 0%˜70%) to give7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-6,9-dicarboxylic acid9-tert-butyl ester 6-methyl ester (Compound AO) as light yellow oil (0.8g, 49%). LC/MS: calc'd 300 (MH+), exp 300 (MH+); ¹HNMR (400 MHz, CDCl₃)δ 1.40-1.45 (m, 9H), 2.29-2.41 (m, 1H), 2.68-2.84 (m, 1H), 3.47-3.79 (m,7H), 3.88-3.96 (m, 0.5H), 4.09-4.16 (m, 0.3H), 4.30-4.45 (m, 1H),4.55-4.67 (m, 0.8H), 11.86 (s, 0.3H).

Step II: To a solution of Compound AO (250 mg, 0.84 mmol) in EtOH (4 mL)was added 40% methyl hydrazine in water (483 mg, 4.2 mmol). The mixturewas sealed and heated at 80° C. for 2 hours. The reaction mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford5-methyl-3-oxo-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6)-ene-12-carboxylicacid tert-butyl ester (Compound AN) as a white solid (99 mg, 40%).LC/MS: calc'd 296 (MH⁺), exp 296 (MH⁺).

Step III: Compound AN (99 mg, 0.33 mmol) was dissolved in DCM/TFA (3 mL,2:1) and stirred at room temperature for 2 hours. The solvent wasremoved and the residue was dried under vacuum to afford5-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6)-en-3-one(Compound AM) as a yellow foam (crude 100 mg, 100%). LC/MS: calc'd 196(MH⁺), exp 196 (MH⁺).

Example 34(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-10-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acidtert-butyl ester (WuXi AppTec (Wuhan) Co., Ltd, CAS: 1160248-56-5)instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Example 35(R)-6-(7-Acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared by the procedure shown below (Scheme 6).

To the solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-carbamic acidtert-butyl ester (PharmaBlock (Nanjing) R&D Co. Ltd, catalog number:PB05636) (106 mg, 0.44 mmol) and Compound C (100 mg, 0.22 mmol) inCH₂Cl₂ (5 mL) was added DIPEA (0.14 mL, 0.44 mmol) at room temperature.The reaction mixture was stirred overnight at room temperature, thendiluted with EtOAc (60 mL). The organic layer was washed with sat.NH₄Cl, sat. NaHCO₃ and brine (20 mL) respectively. The organic layer wasdried over Na₂SO₄, and then concentrated under reduced pressure to givethe crude product which was dissolved in CH₂Cl₂ (5 mL). To the solutionwas added trifluoroacetic acid (2 mL) at 0° C. The mixture was stirredat room temperature for 2 hours. The solvent was removed under reducedpressure to give the crude(R)-6-(7-amino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound AP) which was directly used for next step.

To a solution of Compound AP and DIPEA (0.19 mL, 1.10 mmol) in CH₂Cl₂ (5mL) was added acetyl chloride (31 μl, 0.44 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 hours, and then quenchedwith sat. NH₄Cl, then diluted with EtOAc (60 mL). The organic layer waswashed with sat. NH₄Cl, sat. NaHCO₃ and brine respectively. The organiclayer was dried over Na₂SO₄, and then concentrated, then purified byreverse phase HPLC to give(R)-6-(7-acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Example 35) (36 mg) as a light yellow powder.

Example 36(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 35 with theprocedure shown in Scheme 6 by using methanesulfonyl chloride instead ofacetyl chloride.

Example 37(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(2-methoxymethyl-azetidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 3-oxa-6-azabicyclo[3.1.1]heptane(WuXi AppTec (Wuhan) Co., Ltd, CAS: 286390-20-3) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 38(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(6-oxa-3-aza-bicyclo[3.1.1]hept-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 6-oxa-3-aza-bicyclo[3.1.1]heptaneinstead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methylester.

Example 39(S)-3-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3,6-diaza-bicyclo[3.2.1]octane-7-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using(2-oxa-5-aza-bicyclo[2.2.1]hept-1-yl)-methanol (the corresponding Bocprotected precursor was purchased from WuXi AppTec (Wuhan) Co., Ltd,CAS: 1357351-86-0) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 402-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic acid instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of Literature Known4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic acid (AR)

Step I: To a solution of serine (10.5 g, 100 mmol) in MeOH (100 mL) at0° C. was added thionyl chloride (8.3 g, 5.1 mL, 70 mmol) over 5minutes. After the reaction mixture was allowed to warm to roomtemperature and stirred for 48 hours, it was concentrated to a solidthrough repetitive evaporation with MeOH (3×20 mL), toluene (1×20 mL),and hexane (20 mL). The crude white solid was dissolved in acetylchloride (120 mL), chilled to 0° C., and phosphorus pentachloride (22.5g, 107 mmol) was added. The reaction mixture was allowed to warm to roomtemperature and was stirred for an additional 9 hours. Then the reactionmixture was cooled, and the solid precipitate was filtered and collectedto yield 13.5 g of a light-yellow solid. This solid was suspended in THF(100 mL) and water (5 mL) at 0° C. and reacted with potassium carbonate(27 g, 195 mmol) and benzoyl chloride (26.6 g, 22 mL, 190 mmol) for 1hour at 0° C. The reaction was stirred for 4 hours at room temperature,then diluted with water (600 mL) and chilled to 0° C. overnight. Thesolid formed in this reaction mixture was filtered off and dried toyield methyl 2-benzamido-3-chloro-propanoate (AR1) (11 g, 42%). LC/MS:calc'd 242 (MH⁺), exp 242 (MH⁺).

Step II: A suspension of LiAlH₄ (6.6 g, 0.17 mol) in Et₂O (150 mL) wastreated carefully with AlCl₃ (7.6 g, 0.057 mol) at −5° C. The resultingmixture was stirred for 30 minutes at −5° C., and methyl2-fluoroacrylate (12 g, 0.114 mmol) was added dropwise. The mixture wasstirred at −5° C. for additional 1 hour. Thereafter, an excess of wetNa₂SO₄ was added to decompose excess of AlCl₃. Solid phase was separatedby filtration and Et₂O was carefully removed at atmospheric pressure togive 7.4 g of 40% solution of 2-fluoroprop-2-en-1-ol in Et₂O which wasfurther diluted with CH₂Cl₂ (20 mL). To this solution, DIPEA (6.33 mL,0.036 mol) was added. The resulting solution was cooled to −30° C., andMsCl (2.42 mL, 0.031 mol) was added dropwise. The reaction mixture wasallowed to warm to room temperature, and stirred for additional 1 hour.The mixture was washed with water, 10% solution of citric acid, brine,dried over Na₂SO₄, and evaporated under reduced pressure to give2-fluoroallyl methanesulfonate (AR2) (3.77 g, 0.024 mol, 93%). Theproduct is relatively unstable and has to be used immediately in thenext step.

Step III: A solution of KOtBu (2.35 g, 0.209 mol) in THF (145 mL) wastreated under argon at −78° C. with a solution of methyl methyl2-benzamido-3-chloro-propanoate (AR1) (2.35 g, 9.72 mmol) in THF (60mL), followed by addition of 2-fluoroallyl methanesulfonate (AR2) (1.5g, 9.72 mmol). The reaction mixture was allowed to warm to roomtemperature, stirred for 28 hours, and partitioned between CH₂Cl₂ andH₂O. The organic layer was washed with 10% solution of citric acid,brine, dried over Na₂SO₄, and evaporated under reduced pressure. Thecrude product was purified by flash column chromatography(hexane/EtOAc=9/1) to give methyl2-[benzoyl(2-fluoroallyl)amino]prop-2-enoate (AR3) (633 mg, 2.44 mmol,25%). LC/MS: calc'd 264 (MH⁺), exp 264 (MH⁺).

Step IV: Methyl 2-[benzoyl(2-fluoroallyl)amino]prop-2-enoate (AR3) (380mg, 1.44 mmol), acetophenone (30 mg), benzophenone (40 mg) weredissolved in 25 mL of benzene. The solution formed was irradiated in aquartz reactor by 500 W medium pressure mercury lamp at room temperaturefor 10 hours. The reaction mixture was concentrated, and the residue waspurified by flash column chromatography (hexane/EtOAc=3/1) to givemethyl 1-fluoro-3-methyl-3-azabicyclo[2.1.1]hexane-4-carboxylate (AR4)(240 mg, 0.913 mmol, 63%). LC/MS: calc'd 264 (MH⁺), exp 264 (MH⁺).

Step V: To a solution of methyl1-fluoro-3-methyl-3-azabicyclo[2.1.1]hexane-4-carboxylate (AR4) (150 mg,0.57 mmol) in CH₂Cl₂ (1.0, mL) was added an aqueous of HCl (6.0N, 8.0mL). The reaction mixture was heated to reflux and stirred for 3 hours.After cooled to room temperature, the solution was filtered. Thefiltrate was evaporated in vacuo, and the residue was washed with MeCNto give 4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic acid as a whitesolid (45 mg). LC/MS: calc'd 146 (MH⁺), exp 146 (MH⁺).

Example 41(R)-6-(5-Acetyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 426-(7-Carboxymethyl-3-thia-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using3-thia-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (PharmaBlock(Nanjing) R&D Co. Ltd, CAS: 1205682-24-1) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Example 43(R)-6-(7-Diazirine-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using7-diazirine-3-oxa-9-aza-bicyclo[3.3.1]nonane (Compound AQ) instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of 7-diazirine-3-oxa-9-aza-bicyclo[3.3.1]nonane (CompoundAQ)

Step I & II: 7-Oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acidtert-butyl ester (200 mg, 0.83 mmol) was added to a solution of NH₃/MeOH(4.0 M, 4 mL). The reaction was heated to 60° C. and stirred for 16hours. After the solution was cooled to room temperature, NH₂OSO₃H (94mg, 0.83 mmol) was added. The mixture was stirred at room temperaturefor 2 hours, and then TEA (84 mg, 0.83 mmol) was added. The solution wascooled to 0° C., a solution of I₂ (1.0 M) was added until an orangecolor appeared. The solvent was removed and the residue was dissolved inwater (5 mL). The aqueous layer was extracted with EA (10 mL) threetimes. The combined organic layer was dried over Na₂SO₄. The solvent wasremoved to give crude Compound AQ1 as brown oil (180 mg) which was usedat next step without further purification. LC/MS: calc'd 254 (MH⁺), exp254 (MH⁺).

Step III: To a solution of crude Compound AQ1 (180 mg) in DCM (3.0 mL)was added a solution of HCl/dioxane (4 M, 2.0 mL). After the reactionmixture was stirred at room temperature for 16 hours, the solvent wasremoved and the residue was dissolved in water (3 mL). The aqueoussolution was washed with DCM to remove water insoluble impurity and thewater solution was then lyophilized to give7-diazirine-3-oxa-9-aza-bicyclo[3.3.1]nonane (Compound AQ) as a whitesolid (80 mg). LC/MS: calc'd 154 (MH⁺), exp 154 (MH⁺).

Example 44(R)-4-(2-Chloro-4-fluoro-phenyl)-6-((1R,3R,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using(1R,3R,5S)-8-aza-bicyclo[3.2.1]octan-3-ol (BePharm (Shanghai) Ltd, CAS:14383-51-8) instead of 3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester.

Example 45(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(9-oxa-3,4,11-triaza-tricyclo[5.3.1.0*2,6*]undeca-2(6),4-dien-11-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to compound la in example 1starting from compound C and compound 45c.

Preparation of Compound 45c

Step I: A mixture of compound G (227 mg, 1 mmol) and DMF-DMA (10 mL) washeated to reflux at 110° C. for 48 hours. After the starting materialdisappeared as monitored by LCMS and TLC, the mixture was cooled to roomtemperature and poured into 50 mL ice-water. The mixture was extractedwith ethyl acetate and the combined organic layer was washed with brineand dried over anhydrous Na₂SO₄. The organic solvent was removed to givecompound 45a as crude product, which was directly used for next stepwithout further purification. LC/MS: calc'd 283 (MH⁺), exp 283 (MH⁺).

Step II: The crude compound 45a was dissolved into 15 mL of ethanol. Tothis solution, 0.5 mL hydrazine monohydrate and 3 mL acetic acid wereadded. The reaction mixture was sealed, heated to 110° C. and stirredovernight. The solvents were removed by reduced pressure and the residuewas purified by Prep-HPLC to give white pure product 45b (32 mg, 13%).MS: calc'd (MH⁺) 252, measured (MH⁺) 252¹H NMR (CDCl₃, 400 MHz): 7.30(s, 1H), 5.07 (m, 1H), 4.96 (m, 1H), 3.90 (m, 2H), 3.72 (d, J=10.8 Hz,1H), 3.57 (d, J=10.8 Hz, 1H, 1.49 (s, 9H) ppm.

Step III: To the solution of compound 45b (32 mg, 0.13 mmol) in CH₂Cl₂(4 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred atroom temperature for 1 h. The solvent was removed under reduced pressureto give the crude product 45c (35 mg, 100%) which was directly used fornext step without further purification. LC/MS: calc'd 152 (MH⁺), exp 152(MH⁺).

Example 462-[[(1R,5S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]aceticacid

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by using ethyl2-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yloxy)acetate 46a instead of3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of ethyl 2-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yloxy)acetate46a

Step I: To a solution of benzyl7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate O (200 mg, 0.72mmol) in DCM (4 mL) was added ethyl 2-diazoacetate (202 mg, 1.44 mmol)and Rhodium(II) acetate (319 mg, 0.72 mmol) at 0° C. The resultingmixture was stirred at room temperature for overnight, and then dilutedwith EtOAc. The organic layer was separated, and the aqueous phase wasextracted with EtOAc. The combined organic phases were washed with waterand brine and dried (Na₂SO₄). The organic solvent was removed in vacuoto give the crude product, which was purified by column chromatographyto give the intermediate benzyl7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate(144 mg, 55%). LC/MS: calc'd 364 (MH⁺), exp 364 (MH⁺).

Step II: To a solution of intermediate benzyl7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate(144 mg, 0.40 mmol) in EtOH (10 mL) was added 10% Pd/C (20 mg). Themixture was charged with H₂ and being stirred at room temperature for 2h. The mixture was filtered through a pad of Celite and washed withEtOH. The resulting filtrate was concentrated in vacuo to give compound46a (83 mg, 91%). LC/MS: calc'd 230 (MH⁺), exp 230 (MH⁺); ¹H NMR (MeOD,400 MHz): 4.18 (dd, J=14.0, 6.8 Hz, 2H), 4.13 (s, 2H), 3.74 (m, 1H),3.68 (m, 4H), 2.98 (m, 2H), 2.27 (m, 2H), 1.77 (m, 2H), 1.27 (t, J=7.2Hz, 3H).

Example 472-[[(1R,5S)-9-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]aceticacid

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by using 3,4-di-fluoro-benzaldehyde andethyl 2-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yloxy)acetate instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 48 Methyl(4R)-6-[(6-acetamido-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by usingN-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)acetamide (48b) instead of3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.Preparation of N-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)acetamide 48b

Step I: A mixture of compound G (100 mg, 0.44 mmol), titanium(IV)isopropylate (250 mg, 0.88 mmol) and ammonia in CH₃OH (20 ml, 7N) wasstirred under N₂ in a capped flask at room temperature for 6 h. ThenNaBH₄ (50 mg, 1.32 mmol) was added to the mixture and stirred at roomtemperature for 3 h. The reaction was then quenched by pouring it intoNH₃.H₂O (2M, 20 ml) and extracted with EA. The organic layer was driedover Na₂SO₄ and concentrated. The resulting residue was purified bypre-HPLC to give the product 48a (30 mg, 30%) as white solid. LC/MS:calc'd 229 (MH⁺), exp 229 (MH⁺). ¹HNMR (400 MHz, CDCl₃): 1.48-1.64 (m,12H), 2.51-2.58 (m, 1H), 3.56-3.63 (m, 2H), 3.72-3.89 (m, 3H), 4.04-4.13(m, 2H).

Step II: To the solution of compound 48a (30 mg, 0.13 mmol) and i-PrNEt2(0.22 mL, 1.3 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added AcCl (46 μL,0.65 mmol). The mixture was stirred at room temperature for 1 h,quenched with Sat. NH₄Cl, diluted with EtOAc (50 mL). The organic layerwas separated, washed with sat. NH₄Cl, sat. NaHCO₃ and brine, dried overNa₂SO₄ and concentrated to give a crude residue (30 mg, 86%), which wastreated with 30% TFA in DCM. The mixture was stirred at room temperaturefor 1 h, solvent was evaporated to give a crude product 48b (30 mg, 95%)which was directly used for next step. LC/MS: calc'd 171 (MH⁺), exp 171(MH⁺).

Example 49 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to compound la in Example 1by using compound 49a instead of3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester.

Preparation of 3-oxa-8-azabicyclo[3.2.1]octan-6-ol (49a)

Step I: A mixture of (1R,5R,6R)-tert-butyl6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G7 (racemic,800 mg, 2.51 mmol), 10% Pd/C (300 mg) and MeOH (20 mL) was hydrogenatedunder 50 psi at 40° C. for 24 h. The mixture was filtered through a padof Celite and washed with MeOH. The resulting filtrate was concentratedin vacuo to give compound G8 (520 mg, 91%). LC/MS: calc'd 252 (MH⁺), exp252 (MH⁺); ¹H NMR (METHANOL-d4, 400 MHz): 4.39 (m, 1H), 4.13 (m, 1H),3.75 (m, 1H), 3.60 (d, J=11.2 Hz, 1H), 3.43 (m, 2H), 3.20 (m, 1H), 2.23(m, 1H), 1.68 (m, 1H), 1.39 (s, 9H).

Step II: Compound G8 (100 mg, 0.44 mmol) was dissolved in 4M HCl inDioxane (5 mL). The solution was being stirred at room temperature for 1h, then the solvent was evaporated under reduced pressure to givecompound 49a (70 mg, 95%) as white solid. LC/MS: calc'd 130 (MH⁺), exp130 (MH⁺).

Example 502-[[8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]oxy]aceticacid

The title compound was prepared in analogy to Example 1 with theprocedure shown in Scheme 3 by using ethyl 3-oxobutanoate,2-bromo-4-fluoro-benzaldehyde and ethyl2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yloxy)acetate 50b instead of methylacetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Preparation of ethyl 2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yloxy)acetate(50b)

Step I: To a solution of tert-butyl6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G8 (racemic, 200mg, 0.87 mmol) in DCM (4 mL) was added ethyl 2-diazoacetate (246 mg,1.75 mmol) and Rhodium(II) acetate (386 mg, 0.87 mmol) at 0° C. Theresulting mixture was stirred at room temperature for overnight, andthen diluted with EtOAc. The organic layer was separated, and theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with water and brine and dried (Na₂SO₄). The organic solvent wasremoved in vacuo to give the crude product, which was purified by columnchromatography on silica gel with EtOAc/PE (50:100) to give the compound50a (205 mg, 75%). LC/MS: calc'd 216 (M-Boc+H⁺), exp 216 (M-Boc+H⁺).

Step II: To a solution of (1R,5R,6R)-tert-butyl6-(2-ethoxy-2-oxoethoxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate50a (racemic, 200 mg, 0.63 mmol) in DCM (10 mL) was added HCl/dioxane (2mL, 7 M). The resulting mixture was stirred at room temperature for 2 h.The organic solvent was removed in vacuo to give the compound 50b (150mg, 94%). MS: calc'd (MH⁺) 216, measured (MH⁺) 216; ¹H NMR (CDCl₃, 400MHz): 4.28 (m, 8H), 3.79 (m, 1H), 3.70 (s, 1H), 3.57 (d, J=12.4 Hz, 1H),2.50 (m, 1H), 2.31 (m, 1H), 1.28 (m, 3H).

Example 51 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to compound la in Example 1starting from compound C and compound6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a. Preparation of6-fluoro-3-oxa-8-azabicyclo[3.2.1]octane 51a:

Compound 51a was prepared from tert-butyl6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G8 by treatmentwith DAST (diethylaminosulfur trifluoride) followed by HCl/dioxane toremove the N-Boc protection.

Example 528-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl 3-oxobutanoate,2-bromo-4-fluoro-benzaldehyde and3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylic acid F instead of methylacetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 53 Methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-[[7-(2-hydroxyacetyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 21 by using methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate53b instead of Compound AC. 53b (67 mg, 0.125 mmol) and glycolic acid(20 mg, 0.25 mmol) afforded 14 mg of Example 53.

Preparation of methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate53b

Compound 53b was prepared in analogy to intermediate AC in Example 15,starting from 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acidtert-butyl ester and methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate53a, while 53a was prepared in analogy to compound C in Example 1.

Example 54 Methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-[(7-carbamoyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 18 starting frommethyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate53b (50 mg, 0.09 mmol) and isocyanato(trimethyl)silane (43 mg, 0.37mmol). 37 mg of the title compound was isolated as a light yellowpowder.

Example 552-[(1R,5)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-chloro-3-fluoro-benzaldehyde and(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock (Nanjing)R&D Co. Ltd, PBN20121752, CAS: 1389441-75-1) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 56 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-endo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 56

Step I: To a solution of methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateAP (60 mg, 0.12 mmol) and triethyl-amine (0.05 mL, 0.36 mmol) in DCM (5mL) was added a 0.05 M solution of tert-butyl N-chlorosulfonylcarbamatein DCM (2.5 mL, 0.125 mmol) dropwise at 0° C. The mixture was allowed towarm to room temperature while stirred for 16 h. Then the mixture wasconcentrated in vacuo. The residue was purified by flash silica gelchromatography to afford 0.08 g of the product 56a as a yellow oil(yield was 97%). MS: calc'd (MH⁺) 684, measured (MH⁺) 684.

Step II: To a solution of methyl(4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylsulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate56a (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixturewas stirred at 25° C. for 3 h. The mixture was concentrated in vacuo.The residue was purified by Preparative HPLC to afford 30 mg of theExample 56 as a light yellow powder (yield was 42%).

Example 57 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-endo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate

To a solution of methyl(4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateAP (60 mg, 0.12 mmol) and triethyl-amine (0.17 mL, 1.2 mmol) in DCM (5mL) was added isocyanato(trimethyl)silane (55 mg, 0.48 mmol) dropwise at0° C. The mixture was allowed to warm to room temperature while stirredfor 16 h. Then the mixture was concentrated in vacuo. The residue waspurified by preparative HPLC to afford 30 mg of the Example 57 as alight yellow powder (yield was 45%).

Example 582-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-bromo-4-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 59Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-chloro-3-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 60 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 60

Step I: A mixture of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(222 mg, 0.5 mmol, compound C, tert-butylexo-N-[(1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]carbamate (158 mg,0.65 mmol) and DIPEA (0.26 mL, 1.5 mmol) in dichloromethane (10 mL). Themixture was stirred at 25° C. for 16 h. The mixture was concentrated invacuo. The residue was purified by silica gel chromatography to afford0.3 g of the product 60a as a yellow oil (yield was 99%). MS: calc'd(MH⁺) 606, measured (MH⁺) 606.

Step II: To a solution of methyl(4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60a (300 mg, 0.49 mmol) in DCM (5 mL) was added TFA (2 mL). The mixturewas stirred at 25° C. for 5 h. The mixture was concentrated in vacuo toafford methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60b (240 mg, 96%) which was used for next step without furtherpurification. MS: calc'd (MH⁺) 506, measured (MH⁺) 506.

Step III: To a solution of methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60b (60 mg, 0.12 mmol) and triethyl-amine (0.05 mL, 0.3 mmol) in DCM (5mL) was added methanesulfonyl chloride (0.018 mL, 0.24 mmol) dropwise at0° C. The mixture was allowed to warm to room temperature while stirredfor 1 h. Then the mixture was concentrated in vacuo. The residue waspurified by preparative HPLC to afford 20 mg of the product 60 as alight yellow powder (yield was 28%).

Example 61 Methyl(4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

To a solution of methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60b (60 mg, 0.12 mmol) and triethyl-amine (0.05 mL, 0.3 mmol) in DCM (5mL) was added acetyl chloride (0.018 mL, 0.24 mmol) dropwise at 0° C.The mixture was allowed to warm to room temperature while stirred for 1h, and then concentrated in vacuo. The residue was purified bypreparative HPLC to afford 23 mg of the title compound 61 as a lightyellow powder (yield was 34%).

Example 62 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-exo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate

To a solution of methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60b (60 mg, 0.12 mmol) and triethyl-amine (0.17 mL, 1.2 mmol) in DCM (5mL) was added isocyanato(trimethyl)silane (55 mg, 0.48 mmol) dropwise at0° C. The mixture was allowed to warm to room temperature while stirredfor 3 h. Then the mixture was concentrated in vacuo. The residue waspurified by Preparative HPLC to afford 23 mg of the title compound 62 asa light yellow powder (yield was 34%).

Example 63 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 63

Step I: To a solution of methyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate60b (60 mg, 0.12 mmol) and triethylamine (0.17 mL, 1.2 mmol) in DCM (5mL) was added a 0.05 M solution of tert-butyl N-chlorosulfonylcarbamatein DCM (2.5 mL, 0.125 mmol) dropwise at 0° C. The mixture was allowed towarm to room temperature while stirred for 16 h, and then concentratedin vacuo. The residue was purified by silica gel chromatography toafford 0.08 g of methyl(4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylsulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate63a as a yellow oil (yield was 97%). MS: calc'd (MH⁺) 684, measured(MH⁺) 684.

Step II: To a solution of methyl(4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylsulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate63a (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL), The mixturewas stirred at 25° C. for 3 h, and then concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 14 mg of the titlecompound 63 as a light yellow powder (yield was 20%).

Example 642-[(1R,5S,6S)-8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]aceticacid

The title compound was prepared in analogy to compound la in Example 1starting from methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate53a (73 mg, 0.15 mmol) and 2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)aceticacid (121 mg, 0.7 mmol) 64c. 21 mg of the title compound was isolated bypreparative HPLC as a yellow powder (yield was 16%).

Preparation of 2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)acetic acid 64c

Step I: To a solution of tert-butyl6-oxo-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G (1.43 mL, 8.81mmol) in THF (50 mL) was added NaH (350 mg, 8.81 mmol) at ice-bath.After 15 min, 2-diethoxyphosphorylacetonitrile (1 g, 4.4 mmol) wasadded. The mixture was stirred at 25° C. for 2 h, quenched with water (5mL) and then extracted with ethyl acetate (200 mL) two times. Thecombined organic layers were washed with water (200 mL) three times,dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography to afford 970 mg ofthe product 64a as a white solid (yield was 88%). MS: calc'd (MH⁺) 251,measured (MH⁺) 251.

Step II: A mixture of tert-butyl(6E)-6-(cyanomethylene)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate64a (970 mg, 3.9 mmol) and 10% palladium on active carbon (200 mg) inmethanol (100 mL) was stirred at 25° C. under 30 psi of H₂ pressure for5 hours. Then the catalyst was filtered off and washed with ethylacetate. The filtrate was concentrate in vacuo. The residue was purifiedby silica gel chromatography to afford 180 mg of the product 64b as acolorless oil (yield was 18%). MS: calc'd (MH⁺) 253, measured (MH⁺) 253.

Step III: A solution of tert-butyl(6S)-6-(cyanomethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 64b(180 mg, 0.71 mmol) in Conc. HCl (5 mL) and acetic acid (1 mL) wasstirred at 100° C. for 4 h. Then the mixture concentrated in vacuo toafford 2-[(6S)-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]acetic acid 64c (121mg, 99%) which was used for next step without further purification. MS:calc'd (MH⁺) 172, measured (MH⁺) 172.

Example 65Endo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-chloro-3-fluoro-benzaldehyde and in the three component reaction step,and (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (CAS: 1389441-75-1)instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 66Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-chloro-3-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid in (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 67Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate and2-bromo-4-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 68Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-bromo-3-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 69Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-chloro-3,4-difluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 70 Ethyl(4R)-6-[[(1S,5R)-7-endo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 35 by using ethyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate70a instead of compound C.

Ethyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate70a was prepared in analogy to compound C with procedures shown inExample 1 by using ethyl acetoacetate and 2-bromo-4-fluoro-benzaldehydeinstead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde,respectively.

Example 71 Ethyl(4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

To a solution of ethyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(75 mg, 0.133 mmol) 71a and triethylamine (0.06 mL, 0.4 mmol) in DCM (5mL) was added acetyl chloride (0.018 mL, 0.24 mmol) dropwise at 0° C.The mixture was allowed to warm to room temperature while stirred for 1h. Then the mixture was concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 27 mg of Example 71 as a light yellowpowder (yield was 33%).

Preparation of ethyl(4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate71a

Compound 71a was prepared in analogy to 60b in Example 60 by using ethyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate70a instead of compound C.

Example 72Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-chloro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic (PharmaBlock (Nanjing)R&D Co. Ltd, PB05416) acid (PharmaBlock (Nanjing) R&D Co. Ltd, PB05416)instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 73Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-chloro-3,4-difluoro-benzaldehydeand exo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 74Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-bromo-3-fluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 75Exo-2-[(1S,5R)-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2,3-difluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid instead of methylacetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 76Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-bromo-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 77Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-bromo-benzaldehyde and exo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-aceticacid (PharmaBlock (Nanjing) R&D Co. Ltd, PB05416) instead of methylacetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 78Exo-2-[(1S,5R)-9-[[(48)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-methyl-3,4-difluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Example 793-[(1S,5R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl]-2,2-dimethyl-3-oxo-propanoicacid

A mixture of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(50 mg, 0.1 mmol), 2,2-dimethylpropanedioic acid (prepared as shown inExample 15) (26.4 mg, 0.2 mmol), HATU (48 mg, 0.25 mmol) andtriethyl-amine (0.09 mL, 0.625 mmol) in dichloromethane (5 mL). Themixture was stirred at 25° C. for 16 h, and then concentrated in vacuo.The resulting residue was purified by preparative HPLC to afford 10 mgof the title compound as a white powder (yield was 18%).

Example 80Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-bromo-3,4-difluoro-benzaldehyde andexo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (PharmaBlock(Nanjing) R&D Co. Ltd, PB05416) instead of methyl acetoacetate,2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Examples 81 and 82(1S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid and(1R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid

A mixture of methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 61 mg, 0.138 mmol),3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 0.127mmol) and DIPEA (0.07 mL, 0.4 mmol) in DCM (5 mL) was stirred at 25° C.for 16 h. Then the mixture was concentrated in vacuo. The residue waspurified by preparative HPLC to afford a pair of diastereomers, Example81 and Example 82.

Preparation of 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a

Step I. To a solution of diethyl aminomalonate hydrochloride (17 g, 80mmol) and DIPEA (44 mL, 250 mmol) in DCM (250 mL) was addeddi-tert-butyl dicarbonate (20.8 g, 96 mmol) at ice-bath. The mixture wasallowed to warm to room temperature while stirred for 16 h. Then themixture was concentrated in vacuo. And the residue was extracted withDCM (150 mL) two times. The combined organic layers were washed withsaturated NaHCO₃ (100 mL) three times, dried over anhydrous sodiumsulfate and concentrated in vacuo to afford 22 g of crude productdiethyl 2-(tert-butoxycarbonylamino)propanedioate as a colorless oil(yield was 100%). MS: calc'd (MH⁺) 276, measured (MH⁺) 276.

Step II. To a solution of diethyl2-(tert-butoxycarbonylamino)propanedioate (20 g, 72.7 mmol) in DMF (100mL) was added NaH (3.5 g, 87.3 mmol). The mixture was allowed to warm toroom temperature while stirred for 0.5 h. Then 4-bromo-1-butene (10.8 g,80 mmol) was added. The mixture was stirred at 90° C. for 4 h. Themixture was cooled to room temperature, quenched with water (20 mL), andconcentrated in vacuo. The residue was purified by silica gelchromatography to afford 14.5 g of the product 81b as a brown oil (yieldwas 60%). MS: calc'd (MH⁺) 330, measured (MH⁺) 330.

Step III. To a solution of diethyl2-but-3-enyl-2-(tert-butoxycarbonylamino)propanedioate 81b (14.5 g, 4.4mmol) in DCM (30 mL) was added TFA (10 mL), The mixture was stirred atroom temperature for 16 h, quenched with saturated NaHCO₃ (50 mL) andthen extracted with DCM (150 mL) two times, washed with saturated NaHCO₃(100 mL) three times, dried over anhydrous sodium sulfate andconcentrated in vacuo to afford diethyl2-amino-2-but-3-enyl-propanedioate as a crude product (9.5 g, 94%),which was used for next step without further purification. MS: calc'd(MH⁺) 230, measured (MH⁺) 230.

Step IV. To a mixture of diethyl 2-amino-2-but-3-enyl-propanedioate (9.5g, 41.5 mmol) and K₂CO₃ (17.3 g, 125 mmol) in ACN (250 mL) was addedbenzyl bromide (5.9 mL, 49.8 mmol). The mixture was stirred at 80° C.for 16 h. Then the insoluble solid was filtered off and the filtrate wasconcentrated in vacuo and the residue was extracted with ethyl acetate(200 mL) two times, washed with water (100 mL) three times, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel chromatography to afford 11.3 g of 81c as acolorless oil (yield was 85%). MS: calc'd (MH⁺) 320, measured (MH⁺) 320.

Step V. To a mixture of diethyl2-(benzylamino)-2-but-3-enyl-propanedioate 81c (13.9 g, 43.6 mmol) inTHF (200 mL) was added standard solution of 2 M LiAlH₄ in THF (44 ml)dropwise at ice-bath. The mixture was allowed to warm to roomtemperature for 3 h. Then the reaction mixture was poured into a mixtureof anhydrous sodium sulfate (500 g) and water (50 mL) in ether (300 mL),Then the insoluble solid was filtered off and the filtrate wasconcentrated in vacuo to afford2-(benzylamino)-2-but-3-enyl-propane-1,3-diol (9.4 g, 91%) which wasused for next step without further purification. MS: calc'd (MH⁺) 236,measured (MH⁺) 236.

Step VI. To a solution of 2-(benzylamino)-2-but-3-enyl-propane-1,3-diol(9.4 g, 40 mmol) and imidazole (6 g, 88 mmol) in DCM (150 mL) was addeda solution of tert-butyldimethylsilyl chloride (16.4 mL, 88 mL) in DCM(50 mL) dropwise at ice-bath. The mixture was allowed to warm to roomtemperature while stirred for 16 h. The mixture was quenched with water(100 mL) and then extracted with DCM (100 mL) two times, washed withwater (100 mL) three times, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gelchromatography to afford 17 g ofN-benzyl-1-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]hex-5-en-2-amine81d as a white solid (yield was 92%). MS: calc'd (MH⁺) 461, measured(MH⁺) 461.

Step VII. To a mixture ofN-benzyl-1-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]hex-5-en-2-amine(1.2 g, 2.59 mmol), NaHCO₃ (435 mg, 5.18 mmol) and sodium acetate (637mg, 7.77 mmol) in ACN (100 mL) was added I₂ (658 mg, 2.59 mmol) at roomtemperature. After 3 h, another batch of sodium acetate (637 mg, 7.77mmol) was added. The mixture was stirred at 50° C. for 16 h. Then theinsoluble solid was filtered off and the filtrate was concentrated invacuo. The residue was extracted with ethyl acetate (100 mL) two times,washed with water (100 mL) three times, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by flashsilica gel chromatography to afford 5.7 g of the product 81e as a brownoil (yield was 45%). MS: calc'd (MH⁺) 522, measured (MH⁺) 522.

Step VIII: The mixture of[1-benzyl-5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methylacetate 81e (5.7 g, 10.94 mmol) and 20% palladium hydroxide on activecarbon (1 g) in ethanol (150 mL) was stirred at 50° C. under 2.5 Mpa ofH₂ pressure for 16 hours. Then the catalyst was filtered off and washedwith ethyl acetate. The filtrate was concentrated in vacuo to afford[5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methylacetate 81f (4.48 g, 95%) which was used for next step without furtherpurification. MS: calc'd (MH⁺) 432, measured (MH⁺) 432.

Step VIII: A mixture of[5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methylacetate (4.48 g, 10.4 mmol) and K₂CO₃ (g, mmol) in methanol (50 mL) wasstirred at 25° C. for 2 h. Then the insoluble solid was filtered off andthe filtrate was concentrated in vacuo. And then the residue wasextracted with ethyl acetate (50 mL) two times, washed with water (20mL) three times, dried over anhydrous sodium sulfate and concentrated invacuo to afford[5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methanol81g (4 g, 98%) which was used for next step without furtherpurification. MS: calc'd (MH⁺) 390, measured (MH⁺) 390.

Step IX: A mixture of[5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methanol(2 g, 5.14 mmol) and di-tert-butyl dicarbonate (2.22 g, 10.28 mmol) intoluene (20 mL) was stirred at 90° C. for 4 h. Then the mixture wasconcentrated in vacuo and the residue was extracted with ether (50 mL)two times, washed with saturated NaHCO₃ (50 mL) three times, dried overanhydrous sodium sulfate and concentrated in vacuo to afford 4.26 g ofthe product 81h as a brown oil (yield was 96%). MS: calc'd (MH⁺) 490,measured (MH⁺) 490.

Step X: To a mixture of tert-butyl2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(hydroxymethyl)pyrrolidine-1-carboxylate(400 mg, 0.82 mmol) and 4-dimethylaminopyridine (300 mg, 2.45 mmol) inDCM (20 mL) was added 4-toluenesulfonyl chloride (312 mg, 1.64 mmol) at0° C. The mixture was stirred at 25° C. for 16 h. Then the mixture wasdiluted with DCM (50 mL) and washed with saturated NH₄Cl (50 mL) threetimes, saturated NaHCO₃ (50 mL) three times and water (50 mL) threetimes, dried over anhydrous sodium sulfate and concentrated in vacuo toafford tert-butyl2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate81i (410 mg, 77%) which was used for next step without furtherpurification. MS: calc'd (MH⁺) 644, measured (MH⁺) 644.

Step XI: A mixture of tert-butyl2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate(410 mg, 0.64 mmol) and TBAF (1 M in THF, 4 mL) in THF (2 mL) wasstirred at 50° C. for 16 h. Then the mixture was diluted with ethylacetate (50 mL) and washed with saturated NH₄Cl (50 mL) three times andwater (50 mL) three times, dried over anhydrous sodium sulfate andconcentrated in vacuo to afford isopropyl5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 81j (73mg, 47%) which was used for next step without further purification. MS:calc'd (MH⁺) 244, measured (MH⁺) 244.

Step XII: To a solution of isopropyl5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (73 mg,0.3 mmol) in DCM (mL) was added Dess-Martin (191 mg, 0.45 mmol) atice-bath. The mixture was allowed to warm to room temperature whilestirred for 2 h. Then the mixture was diluted with DCM (50 mL) andwashed with saturated NaHCO₃ (50 mL) three times and water (50 mL) threetimes, dried over anhydrous sodium sulfate and concentrated in vacuo toafford tert-butyl 5-formyl-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate(71 mg, 98%) which was used for next step without further purification.MS: calc'd (MH⁺) 242, measured (MH⁺) 242.

Step XIII: A 50 ml of flask fitted with magnetic stirrer was chargedwith 5 ml of THF and was cooled to −78° C., to which 2-methyl-2-butene(0.15 mL, 3 mmol) was added and stirred for 5 minutes. Another 50 ml offlask fitted with magnetic stirrer was charged with tert-butyl5-formyl-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (71 mg, 0.3 mmol)and tert butanol (5 mL) and was stirred at 25° C., to which the aboveprepared 2-methyl-2-butene THF solution was added. The resulting mixturewas cooled to 0° C., and then a solution of NaH₂PO₄ (81 mg, 0.52 mmol)in water (5 mL) and a solution of NaClO₂ (20 mg, 0.22 mmol) in water (5mL) were added subsequently. After stirring for 20 minutes at 0° C., thereaction mixture was diluted with water (10 mL), acidified to pH 5-6using 1N HCl, and extracted with ethyl acetate (50 mL) three times. Thecombined organic phases were dried over Na₂SO₄, and concentrated invacuo to afford8-tert-butoxycarbonyl-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid81k (40 mg, 51%), which was used for next step without furtherpurification. MS: calc'd (MH⁺) 258, measured (MH⁺) 258

Step XIV: To a solution of8-tert-butoxycarbonyl-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid(40 mg, 0.15 mmol) in DCM (3 mL) was added TFA (1 mL), The mixture wasstirred at room temperature for 4 h. The mixture was concentrated invacuo to afford 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a(20 mg, 85%) which was used for next step without further purification.MS: calc'd (MH⁺) 158, measured (MH⁺) 158.

Example 838-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid

The title compound was prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using ethyl acetoacetate,2-chloro-3-fluoro-benzaldehyde and3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a instead of methylacetoacetate, 2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively.

Examples 84 and 85(1S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid and(1R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid

The title compounds were prepared in analogy to Example 1a with theprocedure shown in Scheme 3 by using 2-methyl-3,4-difluoro-benzaldehydeand 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a instead of2-chloro-4-fluoro-benzaldehyde and3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester,respectively. Purification by HPLC afforded two diastereomers, Example84 and Example 85.

Examples 86 and 872-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 86 and 87

To a solution of 86j, which was one of the two enantiomers of methyl2-exo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, indimethylformamide (5 mL) was added methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 76 mg, 0.17 mmol), potassium iodide (35 mg, 0.21 mmol) andN,N-diisopropylethylamine (0.05 mL). The reaction mixture was heated to55° C. for 3 hours. The reaction mixture was cooled down to roomtemperature, and then NaOH (35 mg, 0.87 mmol) in H₂O (0.5 mL) was added.The mixture was then stirred at room temperature for three hours.Afterwards, the reaction mixture was quenched by adding ice-water, andthen neutralized to pH 7.0 with 1N hydrochloride solution. The mixturewas extracted with ethyl acetate (50 mL) three times. The organic phasewas separated and concentrated. The residue was purified by silica gelchromatography and then by prepare-HPLC to give Example 86 (18 mg, 22%).

Example 87 was prepared in analogy to Example 86 starting from 86k,which was the other enantiomer of methyl2-exo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC.

Preparation of the Two Enantiomers of methyl2-exo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 86j and 86k

Step I: To a mixture of8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (prepared according tothe procedure reported in Journal of Heterocyclic Chemistry 1992, 29(6),1541-4; 46.2 g, 0.2 mol, 1.0 eq) and imidazole (16.3 g, 0.24 mol, 1.2eq) in DCM (500 mL) was added TBSCl (33.1 g, 0.22 mol, 1.1 eq) in DCM(100 mL) slowly at room temperature in 10 min, then the mixture wasstirred at room temperature for 2 h, washed with water (300 mL) andbrine (300 mL), the organic layer was dried over Na₂SO₄ and concentratedto give8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-one86a as a colorless oil, 62 g, yield: 90%. MS: calc'd (MH⁺) 232, measured(MH⁺) 232.

Step II: To a suspension of NaH (6.98 g, 173 mmol) in tetrahydrofuran(460 mL) at 0° C. was added dropwise a solution of diethylcyanomethylphosphonate (18.5 mL, 103.8 mmol) in tetrahydrofuran (80 mL).The reaction was refluxed for 1 hour and then cooled at 0° C. again. Tothe reaction mixture was added a solution of compound 86a (26.0 g, 75mol) in tetrahydrofuran (80 mL). The reaction was allowed to warm up toroom temperature and stirred 2 hours. The reaction mixture was thenquenched with saturated aqueous solution of NaHCO₃, and most of the THFwas removed under reduced pressure. Ethyl acetate (200 mL) was added,washed with water, brine, dried over Na₂SO₄ and evaporated to dryness.The residue was purified on silica gel, eluting with 0 to 20% EtOAc inhexanes, to give the desired product(2E)-2-[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ylidene]acetonitrile86b (27 g, 98%). MS: calc'd (MH⁺) 369, measured (MH⁺) 369.

Step III: A solution of compound 86b (27.8 g, 75.3 mmol) in anhydrousmethanol (300 mL) was placed in a flask equipped with a condenser, to itwas added Mg (2 g, 87 mmol). The reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was then cooled withice-water bath. After another 1 h stirring, another batch of Mg (2 g, 87mmol) was added, and the reaction mixture was allowed to stir for 2hours at 0° C. The mixture was diluted with ethyl acetate (500 mL), andquenched by adding slowly 12 N HCl (13 mL). The solvents were removedunder reduced pressure, and the residue was dissolved in ethyl acetate(500 mL), which was then washed with water, brine, dried over Na₂SO₄ andevaporated to dryness. The above procedure was repeated until compound86b was completely consumed. A crude product (14 g) with2-exo-[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-yl]acetonitrile86c as the major product was obtained, and used without furtherpurification in the next step. Around 20% of the endo-isomer wasobserved.

Step IV: The crude 86c (14 g) was dissolved in 1N HCl in methanol (350mL). The reaction mixture was stirred at room temperature for 4 hours.The solvent was evaporated under reduced pressure. Ethyl acetate (300mL) and water (50 mL) were added, and basified with 2N NaOH aqueoussolution to pH 10. The organic phase was separated and the aqueous phasewas extracted with ethyl acetate 3 times. The combined organic layerswere washed with brine, dried over MgSO₄ and evaporated to dryness. Theresidue was dissolved in DCM (200 mL), and DMP (23 g, 56.5 mmol) wasadded. After stirred overnight, 20 mL of water was added, and the solidin the reaction mixture was filtered off. The filtrate was extractedwith DCM. The organic layers were combined and washed with water, brine,dried over Na₂SO₄, and concentrated under reduced pressure. The crudeproduct was purified on silica gel, eluting with 0 to 50% EtOAc inhexanes, to give the desired product2-exo-(8-benzyl-6-oxo-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile 86d (8g). Around 10% of the endo-isomer was observed.

Step V: To a stirred solution of compound 86d (8 g, 31.3 mmol) in 20 mLof dichloromethane was added diethylaminosulfur trifluoride (12 mL, 94mmol). The mixture was stirred at 50° C. overnight, then quenched withsaturated NaHCO₃ aqueous solution at 0° C., and extracted three timeswith DCM (100 mL). The combined organic layers were washed with water,brine, dried over anhydrous MgSO₄, filtered, concentrated and purifiedby silica gel column chromatography (EtOAc/Hexane 5:95) to yield2-exo-(8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile86e (7 g, 81%).

Step VI: Acetyl chloride (48 mL) was added into methanol (100 mL) at 0°C., and the mixture was stirred at room temperature for 1 hour. To itwas added compound 86e (2 g, 7.2 mmol), and the resulting mixture wasstirred for 18 hours at 80° C. After cooling to room temperature, thesolvents were removed under reduced pressure. The residue was dissolvedin ethyl acetate, neutralized carefully with aqueous NaHCO₃ solution.The organic phase was washed with brine, dried over Na₂SO₄ andevaporated to dryness. The crude mixture was purified on silica gel togive methyl2-exo-(8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetate (2 g,88%), which was further purified by chiral SFC (ChiralCel OJ 250*30 mm,Sum 15% ethanol) to give a pair of enantiomers of methyl2-exo-[8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 86h(peak 1) and 86i (peak 2).

Step VII: To a solution of 86h (2 g 6.4 mmol) in 15 mL of methanol wasadded 200 mg of Pd(OH)₂ (20% loading on carbon, wet with 50% watercontent). The mixture reaction was stirred at room temperature under 1atm H₂ for 6 h, and then filtered, and washed with additional methanol.The filtrates were concentrated under reduced pressure to yield one ofthe two enantiomers of methyl2-exo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 86j (1.26 g).

The other enantiomer of methyl2-exo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 86k, wasprepared in analogy to 86j from 86i.

Examples 88 and 892-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 88 and 89

Example 88 was prepared in analogy to Example 86 starting from 86j (30mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate88a (76 mg). 18 mg of the title compound 88 was isolated afterpurification by preparative HPLC. Methyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate88a was prepared in analogy to compound C with procedures shown inExample 1 by using 2-chloro-3-fluoro-benzaldehyde instead of2-chloro-4-fluoro-benzaldehyde in the three component reaction.

Example 89 was prepared in analogy to Example 86 starting from 86k (30mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate88a (76 mg). 14 mg of compound 89 was isolated after purification bypreparative HPLC.

Examples 90 and 912-[(1R,3S,5S)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 90 and 91

Example 90 was prepared in analogy to Example 86 starting from 86j andmethyl(4R)-6-(bromomethyl)-4-(2-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate90a. Methyl(4R)-6-(bromomethyl)-4-(2-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate90a was prepared in analogy to compound C with procedures shown inExample 1 by using 2-chlorobenzaldehyde instead of2-chloro-4-fluoro-benzaldehyde in the three component reaction.

Example 91 was prepared in analogy to Example 86 starting from 86k andmethyl(4R)-6-(bromomethyl)-4-(2-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate90a.

Examples 92 and 922-[(1R,3S,5S)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 92 and 93

Example 92 was prepared in analogy to Example 86 starting from 86j andethyl(4R)-6-(bromomethyl)-4-(2-bromophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate92a.(4R)-6-(bromomethyl)-4-(2-bromophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate92a was prepared in analogy to compound C with procedures shown inExample 1 by using ethyl acetoacetate and 2-bromobenzaldehyde instead ofmethyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde in the threecomponent reaction.

Example 93 was prepared in analogy to Example 86 starting from 86k andethyl(4R)-6-(bromomethyl)-4-(2-bromophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate92a.

Examples 94 and 952-[(1R,3S,5S)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 94 and 95

Example 94 was prepared in analogy to Example 86 starting from 86j (30mg) and methyl(4R)-4-(2-bromo-3-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate94a (86 mg). 13 mg of the title compound was isolated.

Methyl(4R)-4-(2-bromo-3-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate94a was prepared in analogy to compound C with procedures shown inExample 1 by using 2-bromo-3-fluorobenzaldehyde instead of2-chloro-4-fluoro-benzaldehyde.

Example 95 was prepared in analogy to Example 86 starting from 86k (30mg) and methyl(4R)-4-(2-bromo-3-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate94a (86 mg). 56 mg of the title compound was isolated.

Examples 96 and 972-[(1R,3S,5S)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(48)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 96 and 97

Example 96 was prepared in analogy to Example 86 starting from 86j (30mg) and methyl(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate96a (78 mg). 12 mg of Example 96 was isolated. Methyl(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate96a was prepared in analogy to compound C with procedures shown inExample 1 by using 4-chloro-3-fluorobenzaldehyde instead of2-chloro-4-fluoro-benzaldehyde in the three component reaction step.

Example 97 was prepared in analogy to Example 86 starting from 86k (30mg) and methyl(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate96a (78 mg). 14 mg of the title compound was isolated.

Examples 98 and 992-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 98 and 99

Example 98 was prepared in analogy to Example 86 starting from 86j (30mg) and ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a (80 mg). 25 mg of Example 98 was isolated. Ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a was prepared in analogy to compound C with procedures shown inExample 1 by using ethyl acetoacetate and 2-chloro-3-fluorobenzaldehydeinstead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde,respectively.

Example 99 was prepared in analogy to Example 86 starting from 86k (30mg) and ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a (80 mg). 25 mg of the title compound was isolated.

Examples 100 and 1012-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compounds were prepared in analogy to Example 86 starting frommethyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (100mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate88a (208 mg). The crude product was purified by silica gelchromatography first, and then by preparative HPLC to give Example 101and Example 102.

Preparation of methyl2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a

Step I: 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (CAS1126795-00-3) (10 g) was dissolved in 200 ml of dichloromethane whichwas cooled to 0° C. Then, CbzCl (14.3 g, 84.7 mmol) was added to themixture followed by the dropwise addition of a solution of TEA (14.6 ml,112.8 mmol) in 20 ml of dichloromethane. The mixture was allowed to warmup to room temperature. After stirring 2 h, it was quenched with 20 mlof a saturated aqueous solution of NaHCO₃. The two layers were separatedand the aqueous layer was extracted with dichloromethane (3×150 ml). Thecombined organic layers were washed with water, dried over Na₂SO₄ andthe solvent was evaporated under reduced pressure. The crude product waspurified by chromatography on silica gel, yielding 10.1 g of benzyl7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100b (64%).

Step II: To a solution of benzyl7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100b (7.6 g, 27.6mmol) in methanol (150 mL) at 0° C. was added Accufluor NFTh (17.5 g,55.2 mmol). The reaction was stirred at 90° C. for 3 hours and thencooled to room temperature. After filtration, the filtrate wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate (20 mL), washed with water and brine, dried over Na₂SO₄and evaporated to dryness. The crude mixture was purified on silica gel,eluting with 0 to 50% EtOAc in hexanes, to give the desired productbenzyl 6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100c(4.1 g, 50%). MS: calc'd (MH⁺) 294, measured (MH⁺) 294.

Step III: To a solution of NaH (273 mg, 11.4 mmol) in tetrahydrofuran(30 mL) at 0° C. was added dropwise a solution of methyl2-dimethoxyphosphorylacetate (2.1 g, 11.4 mmol) in tetrahydrofuran (10mL). The reaction was stirred at 70° C. for 1 hour and then cooled to 0°C. again. To the reaction mixture was added a solution of benzyl6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100c (1.7g, 5.7 mmol) in tetrahydrofuran (8 mL). The reaction was allowed to warmup to room temperature and stirred 2 hours. After being quenched with 1N HCl, the solvent was evaporated under reduced pressure. Ethyl acetate(20 mL) was added. The mixture was washed with water, brine, dried overNa₂SO₄ and evaporated to dryness. The crude mixture was purified onsilica gel, eluted with 0 to 20% EtOAc in hexanes, to give the desiredproduct benzyl(7Z/E)-6-fluoro-7-(2-methoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate100d (1.8 g, 89%). MS: calc'd (MH⁺) 350, measured (MH⁺) 350.

Step IV: To a solution of(7Z/E)-6-fluoro-7-(2-methoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate100d (1.8 g, 5.1 mmol) in THF (50 ml) and H₂O (2 ml) was add of PtO₂(250 mg, 1.1 mmol). The mixture reaction was stirred at room temperatureunder hydrogen balloon for 6 h, then filtered and washed with additionalTHF. The filtrates were concentrated under reduced pressure to yieldmethyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (910mg, 70%).

Examples 102 and 1032-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compounds were prepared in analogy to Example 86 starting frommethyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (100mg) and ethyl(4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate102a (215 mg). The crude product was purified by silica gelchromatography first, and then by preparative HPLC to give Example 102(27 mg), and Example 103 (21 mg). Ethyl(4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate102a was prepared in analogy to compound C with procedures shown inExample 1 by using ethyl acetoacetate and 2-chloro-benzaldehyde insteadof methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde in the threecomponent reaction.

Example 104(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4,10-dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6]dodeca-2,5-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a in Scheme 3 byusing methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC (200 mg) and4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (100mg). 15 mg of the title compound was isolated as yellow powder.

Preparation of4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a

Step I: A solution of tert-butyl7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol, 1.0eq) and NH₂OH.HCl (462 mg, 3 mmol, 3.0 eq) in EtOH (10 mL) was refluxedfor 2 h. The reaction mixture was concentrated to give tert-butyl7-hydroxyimino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 104b as awhite solid, which was used in next step without further purification.MS: calc'd (MH⁺) 267, measured (MH⁺) 267.

Step II: To a solution of compound 104b (512 mg, 2 mmol, 1.0 eq) in THF(10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After30 min, dry DMF (740 mg, 10 mmol, 5.0 eq) in THF (2 mL) was addeddropwise, the mixture was stirred for another 2 h from −60° C. to roomtemperature. To it 12 N HCl (1 mL) was added and refluxed for 2 h. Thereaction mixture was concentrated to give4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (332mg) as an oil. MS: calc'd (MH⁺) 167, measured (MH⁺) 167.

Example 105(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a in Scheme 3 byusing methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC (200 mg) and5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a(100 mg). 20 mg of the title compound was isolated as yellow powder.

Preparation of5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a

A solution of tert-butyl7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol) andtert-butoxy-N,N,N′,N′-tetra-methyl-methanediamine (522 mg) in dioxane(10 mL) was stirred at 60° C. for 16 h. The solvent was removed invacuo, and the residue was dissolved in EtOH (10 mL). To it NH₂OH.HCl(462 mg, 3 mmol) was added. After stirring at room temperature for 2 h,12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture wasconcentrated to give5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a asan oil (yield 100%), which was used without further purification. MS:calc'd (MH⁺) 167, measured (MH⁺) 167.

Example 106(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carrboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a in Scheme 3 byusing methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC (200 mg) and7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene106a (140 mg). 8 mg of the title compound was isolated as yellow powder.

Preparation of7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien106a

Step I: To a stirred solution of potassium hydroxide (730 mg, 13 mmol)in dry MeOH (50 mL) at 0° C. under nitrogen was added a solution of9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (CAS: 81514-40-1, 1 g, 4.3mmol) in dry MeOH (20 mL) dropwise over 10 min. The reaction mixture wasstirred at 0° C. for another 10 min, and PhI(OAc)2 (1.83 g, 5.5 mmol)was added portion wise over 10 min. The reaction mixture was warmed toroom temperature, with stirring, overnight. After the starting materialdisappeared as monitored by TLC, MeOH was removed under reduced pressureand the residue was cooled to 0° C. and 10 ml of 6N HCl was addedcarefully. The mixture was stirred at room temperature for 2 hours, andthen ethyl acetate and water (50 mL, 1:1) were added. The aqueous layerwas separated and was added into K₂CO₃ till the solution was saturated.The mixture was extracted with ethyl acetate (20 mL) three times, driedand concentrated, the residue was purified by silica gel (EA/PE=1:2) togive 9-benzyl-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 106b ascolorless oil, 270 mg, yield: 25%. MS: calc'd (MH⁺) 248, measured (MH⁺)248.

Step II: A mixture of compound 106b (247 mg, 1 mmol, 1.0 eq), Boc₂O (654mg, 3 mmol, 3.0 eq) and Pd/C (50 mg, 20%) in MeOH (10 mL) was stirred atroom temperature for 16 h. Then the solid was filtered off, the solventwas removed in vacuo, the residue was purified by silica gel (EA/PE=1:1)to give tert-butyl6-hydroxy-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 106c as acolorless oil. 260 mg, yield: 100%. MS: calc'd (MH⁺) 258, measured (MH⁺)258.

Step III:7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylicacid tert-butyl ester 106d was prepared in analogy to compound 105a inExample 105, starting with 106c (260 mg). 141 mg of 106d was obtained asa colorless oil. MS: calc'd (MH⁺) 283, measured (MH⁺) 283.

Step IV: To a solution of7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylicacid tert-butyl ester 106d (141 mg, 0.5 mmol, 1.0 eq) in DCM (5 mL) wasadded DAST (166 mg, 1 mmol, 2.0 eq) at −78° C. Then mixture was stirredfor 6 h from −78° C. to room temperature. The reaction was diluted withEA (20 mL), and washed with aqueous NaHCO₃ (5%, 20 mL). The organiclayer was dried and concentrated to give7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylicacid tert-butyl ester as an oil, 150 mg, crude yield: 100%. MS: calc'd(MH⁺) 285, measured (MH⁺) 285.

Step V: A solution of7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylicacid tert-butyl ester (150 mg) in TFA/DCM (5 mL, 1:2) was stirred atroom temperature for 1 h. The solvent was removed in vacuo to give7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene106a (141 mg) as yellow oil, crude yield: 100%. MS: calc'd (MH⁺) 185,measured (MH⁺) 185.

Example 107(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7,7-difluoro-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-arboxylicacid methyl ester

The title compound was prepared in analogy to Example 1a in Scheme 3 byusing methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC (100 mg) and7,7-difluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene107a (50 mg). 8 mg of the title compound was isolated as yellow powder.

Preparation of7,7-difluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene107a

Step I: A solution of 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride(CAS 1126795-00-3, 2.82 g), TEA (6.12 g, 60 mmol, 3.0 eq) and2-Nitro-benzenesulfonyl chloride (8.84 g, 40 mmol, 2.0 eq) in DCM (100mL) was stirred at room temperature for 10 h. Then the solvent wasremoved in vacuo, the residue was purified by silica gel (EA/PE=1:3) togive 9-(2-nitrophenyl)sulfonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 107bas a white solid, 4.90 g, yield: 75%. MS: calc'd (MH⁺) 327, measured(MH⁺) 327.

Step II: A mixture of compound 107b (4.9 g, 15 mmol, 1.0 eq) andtert-butoxy-N,N,N′,N′-tetra-methyl-methanediamine (3.92 g, 22.5 mmol,1.5 eq) in dioxane (50 mL) was stirred at 60° C. for 16 h, then thesolvent was removed in vacuo, the residue was dissolved in EtOH (50 mL),NH₂NH₂.H₂O (3.5 mg, 75 mmol, 5.0 eq) was added and then stirred at 60°C. for 2 h. The reaction mixture was concentrated and then purified bysilica gel (EA/PE=1:2) to give12-(2-Nitro-benzenesulfonyl)-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene107c as a slight yellow oil, 1.57 g, yield: 29.8%. MS: calc'd (MH⁺) 351,measured (MH⁺) 351.

Step III: A solution of CrO₃ (100 mg, 1.0 mmol, 0.33 eq) and H₅IO₆ (2.05g, 9 mmol, 3.0 eq) in MeCN (50 mL) was stirred at room temperature for 5min, compound 107c (1.05 g, 3 mmol, 1.0 eq) in MeCN (5 mL) was added andthen stirred at 70° C. for 12 h. The solid was filtered off and thefiltrate was diluted with EA (50 mL), washed with Na₂S₂O₃ (10%, 50 mL)and brine (50 mL). The organic layer was concentrated, and the residuewas purified by silica gel (EA/PE=1:2) to give12-(2-nitro-benzenesulfonyl)-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-7-one107d as a white solid, 270 mg, yield: 25%. MS: calc'd (MH⁺) 365,measured (MH⁺) 365.

Step IV: A mixture of compound 107d (270 mg, 0.74 mmol, 1.0 eq) and DAST(1 mL, 7.4 mmol, 10.0 eq) in DCM (1 mL) was stirred at 60° C. in sealedtube for 18 h. The mixture was added dropwise to a cooled aqueous NaHCO₃(20 mL, 5%) solution, then the mixture was extracted with EA (20 mL) twotimes, the organic layer was dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel (EA/PE=1:3) to give7,7-difluoro-12-(2-nitro-benzenesulfonyl)-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene107e as a slight yellow oil. 100 mg, yield: 35%. MS: calc'd (MH⁺) 387,measured (MH⁺) 387.

Step V: To a mixture of compound 107e (100 mg, 0.26 mmol, 1.0 eq) andLiOH (33 mg, 0.78 mmol, 3.0 eq) in DMF (5 mL) was added mercaptoaceticacid (36 mg, 0.4 mmol, 1.5 eq) slowly, the mixture was stirred at roomtemperature for 3 h. The solvent was removed in vacuo to give7,7-difluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene107a as an oil, used in next step without further purification. MS:calc'd (MH⁺) 202, measured (MH⁺) 202.

Example 108 Methyl(4R)-4-(2-chloro-4-fluorophenyl)-6-[(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1a in Scheme 3 byusing methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 100 mg) and 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane108a (200 mg). 6 mg of the title compound was isolated as yellow powder.

Preparation of 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane 108a

Step I: A mixture of compound G (227 mg, 1 mmol, 1.0 eq) in HCl/Dioxane(2 mL) was stirred at room temperature for 2 h. Then the solvent wasremoved in vacuo to give 3-oxa-8-azabicyclo[3.2.1]octan-6-one 108b aswhite solid (200 mg), which was used in the next step without furtherpurification. MS: calc'd (MH⁺) 128, measured (MH⁺) 128.

Step II: A mixture of compound 108b (100 mg), TEA (102 mg), K₂CO₃ (207mg, 1.5 mmol, 3.0 eq) and 2-nitro-benzenesulfonyl chloride (222 mg) inMeCN (10 mL) was stirred at room temperature for 10 h. Then the solventwas removed in vacuo, the residue was purified by silica gel (EA/PE=1:3)to give 8-(2-nitrophenyl)sulfonyl-3-oxa-8-azabicyclo[3.2.1]octan-6-one108c as a white solid, 100 mg. MS: calc'd (MH⁺) 313, measured (MH⁺) 313.

Step III: A mixture of compound 108c (100 mg) and DAST (1 mL) in DCM (1mL) was stirred at 50° C. in sealed tube for 18 h. The mixture was addeddropwise to a cooled aqueous NaHCO₃ (20 mL, 5%) solution, then themixture was extracted with EA (20 mL) two times, the organic layer wasdried (Na₂SO₄) and concentrated. The residue was purified by silica gel(EA/PE=1:3) to give6,6-difluoro-8-(2-nitrophenyl)sulfonyl-3-oxa-8-azabicyclo[3.2.1]octane108d as a slight yellow oil. 90 mg. MS: calc'd (MH⁺) 335, measured (MH⁺)335.

Step IV: To a solution of compound 108d (90 mg) and LiOH (36 mg) in DMF(5 mL) was added mercaptoacetic acid (36 mg) slowly, the mixture wasstirred at room temperature for 3 h. The solvent was removed in vacuo togive 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane 108a as an oil, whichwas used in next step without purification. MS: calc'd (MH⁺) 150,measured (MH⁺) 150.

Examples 109 and 1102-[(1R,3R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 109 and 110

Example 109 was prepared in analogy to Example 86 by using(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 45 mg) and 109a (one of the two enantiomers of methyl2-endo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 22 mg). 22mg of Example 109 was isolated as yellow powder.

Example 110 was prepared in analogy to Example 86 by using(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 44 mg) and 109b (the other enantiomer of methyl2-endo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate-3-yl]acetate,22 mg). 20 mg of Example 110 was isolated as yellow powder.

Preparation of the Two Enantiomers of methyl2-endo-[(6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 109a and109b

Step I: To a solution of Trimethyl phosphoroacetate (36.4 g, 0.2 mol,2.0 eq) in THF (800 mL) was added NaH (8 g, 0.2 mol, 2.0 eq) slowly atroom temperature, then the mixture was refluxed for 1 h. After thereaction was cooled to room temperature, compound 86a (34.5 g, 0.1 mol,1.0 eq) in THF (150 mL) was added dropwise and then refluxed for 16 h.The mixture was quenched with water, extracted with EA (500 mL) twotimes, the organic layers were combined, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel (EA/PE=1:10) togive methyl(2E/Z)-2-[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ylidene]acetate109c as a white solid, 34 g, yield: 85%. ¹H NMR (400 MHz, DMSO-d6) δ:7.45-7.11 (m, 5H), 5.75 (s, 0.6H), 5.70 (s, 0.4H), 4.13-3.99 (m, 1H),3.99-3.82 (m, 2H), 3.66-3.53 (m, 3H), 3.52-3.45 (m, 1H), 3.45 (br, 1H),3.35-3.29 (m, 1H), 3.07 (br, 1H), 2.53 (br, 1H), 2.27 (d, J=15.6 Hz,0.4H), 2.13 (d, J=14.0 Hz, 0.6H), 1.94-1.76 (m, 2H), 0.91-0.81 (m, 9H),0.06-0.07 (m, 6H); MS: calc'd (MH⁺) 402, measured (MH⁺) 402.

Step II: A mixture of compound 109c (32 g, 0.08 mol, 1.0 eq) andPd(OH)₂/C (3 g, 15%) in MeOH (800 mL) was stirred at 60° C. for 20 hunder 1 atm hydrogen, then the mixture was filtered, the filtrate wasconcentrated to give methyl2-[6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ylidene]acetate109d as a colorless oil, 22.4 g, yield: 90%. ¹HNMR (400 MHz, DMSO-d6) δ:4.21 (dd, J=1.8, 6.4 Hz, 1H), 3.58 (s, 3H), 3.45 (t, J=6.8 Hz, 1H), 3.03(d, J=6.0 Hz, 1H), 2.31-2.24 (m, 2H), 2.17-2.08 (m, 1H), 2.03 (dd,J=6.0, 13.6 Hz, 1H), 1.98-1.82 (m, 2H), 1.53 (dd, J=7.8, 13.6 Hz, 1H),1.10-0.95 (m, 2H), 0.89-0.84 (m, 9H), 0.07-0.02 (m, 6H); MS: calc'd(MH⁺) 312, measured (MH⁺) 312.

Step III: To a solution of compound 109d (40 g, 0.13 mol, 1.0 eq) andTEA (40 g, 0.39 mol, 3.0 eq) in DCM (800 mL) was added a solution ofCbzCl (45 g, 0.26 mol, 2.0 eq) in DCM (150 mL) slowly. The resultingmixture was stirred at room temperature for 16 h. The mixture wasquenched with water, washed with 1N HCl (500 mL), the organic layer wasdried over Na₂SO₄ and concentrated to give benzyl6-[tert-butyl(dimethyl)silyl]oxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate109e as a crude product.

Step IV: crude 109e was dissolved in MeOH (400 mL), 12 N HCl (40 mL, 3.0eq) was added and then stirred at room temperature for 30 min. Themixture was diluted with water (800 mL), and extracted two times with EA(500 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated, the residue was purified by silica gel (EA/PE=1:3) to givebenzyl6-hydroxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate109f as a colorless oil, 30 g, yield for two steps, 70%. ¹H NMR (400MHz, DMSO-d6) δ: 7.43-7.26 (m, 5H), 5.09 (s, 2H), 4.90 (dd, J=3.6, 6.8Hz, 1H), 4.23 (d, J=6.4 Hz, 1H), 4.16-4.09 (m, 1H), 4.12-3.92 (m, 1H),3.59 (s, 3H), 2.38 (d, J=7.2 Hz, 2H), 2.14-1.93 (m, 5H), 1.72 (br, 1H);MS: calc'd (MH⁺) 334, measured (MH⁺) 334.

Step V: To a solution of compound 109f (30 g, 0.09 mol, 1.0 eq) in DCM(800 mL) was added DMP (Dess-Martin Periodinane, 76.5 g, 0.18 mol, 2.0eq) slowly at 0° C. The resulting mixture was stirred at roomtemperature for 16 h, and quenched with water. The solid was filteredoff, the filtrate was washed with brine (500 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel (EA/PE=1:3) to givebenzyl3-(2-methoxy-2-oxo-ethyl)-6-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate109g as a colorless oil (26.5 g, yield 88%). ¹H NMR (400 MHz, DMSO-d6)δ: 7.46-7.30 (m, 5H), 5.15 (s, 2H), 4.61 (br, 1H), 4.00 (br, 1H), 3.58(s, 3H), 2.77 (dd, J=7.2, 18.2 Hz, 1H), 2.41-2.30 (m, 3H), 2.28-2.10 (m,3H), 1.49 (d, J=13.2 Hz, 1H), 1.38 (d, J=11.8 Hz, 1H); MS: calc'd (MH⁺)332, measured (MH⁺) 332.

Step VI: A mixture of compound 109g (16 g, 0.04 mol, 1.0 eq) and DAST(32 g, 0.2 mol, 5.0 eq) in DCM (30 mL) was stirred at 60° C. in sealedtube for 3 days. The mixture was added dropwise to a cooled aqueousNaHCO₃ (500 mL, 5%) solution, then the mixture was extracted with EA(300 mL) two times, the organic layers were combined, washed with 1N HCl(200 mL) and brine (300 mL), dried over Na₂SO₄ and concentrated. Thecrude product contained the desired difluorinated product and abyproduct, vinyl fluoride in a ratio of about 1:1. The crude product wasdissolved in DCM (200 mL), to it m-CPBA (20 g, 0.12 mol, 3.0 eq) wasadded slowly. The reaction mixture was stirred at room temperature for16 h. the solid was filtered off, the filtrate was washed with NaHCO₃(200 mL, 5% aq. solution) three times, Na₂S₂O₃ (200 mL, 5% aqueoussolution) two times and brine (300 mL). The organic layer wasconcentrated and purified by preparative HPLC to remove the epoxidederived from vinyl fluoride. The obtained difluoro-product was furtherpurified by chiral SFC (ChiralPak AD 250*30 mm, 5 um, 15% ethanol) togive a pair of enantiomers of benzyl6,6-difluoro-3-endo-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,109h (2 g, peak 1), and 109i (2 g, peak 2).

Step VII: A mixture of 109h (2 g, 5.5 mmol, 1.0 eq) and Pd(OH)₂/C (200mg, 10%) in MeOH (30 mL) was stirred at room temperature for 16 h underhydrogen, then the mixture was filtered, the filtrate was concentratedto give one of the two enantiomers of methyl2-endo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 109a, as acolorless oil (1.15 g, yield 92%). ¹H NMR (400 MHz, DMSO-d6) δ: 3.58 (s,3H), 3.47 (t, J=7.4 Hz, 1H), 3.29-3.18 (m, 1H), 2.77 (br, 1H), 2.37-2.16(m, 4H), 2.12-1.85 (m, 3H), 1.36 (dd, J=7.0, 14.2 Hz, 1H), 1.10 (dd,J=6.4, 13.6 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d6) d=(−87.44)-(−89.12) (m,1F), (−107.59)-(−109.06) (m, 1F). MS: calc'd (MH⁺) 220, measured (MH⁺)220.

The other enantiomer of methyl2-endo-[6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetate, 109b, wasprepared from 109i in analogy to 109a.

Examples 111 and 1122-[(1R,3R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 111 and 112

Example 111 was prepared in analogy to Example 86 starting from methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate111a (50 mg) and 109a (22 mg). 4 mg of Example 111 was isolated asyellow powder.

Methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate111a was prepared in analogy to compound C with procedures shown inExample 1 by using 3,4-difluoro-2-methyl-benzaldehyde instead of2-chloro-4-fluoro-benzaldehyde.

Example 112 was prepared in analogy to Example 86 starting from methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate111a (50 mg) and 109b (22 mg). 3.5 mg of Example 112 was isolated asyellow powder.

Example 1132-[(1R,3R,58)-8-[[(48)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid or2-[(1S,3S,5R)-8-[[(48)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

The title compound was prepared in analogy to Example 86 starting frommethyl(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate96a (50 mg) and 109a (22 mg). 15 mg of the title compound was isolatedas yellow powder.

Examples 114 and 1152-[(1R,3S,5S)-8-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(1S,3R,5R)-8-[[(4S)-4-(3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

Preparation of Examples 114 and 115

Example 114 was prepared in analogy to Example 86 starting from 86j (22mg) and methyl(4S)-6-(bromomethyl)-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate114a (50 mg). 6 mg of Example 114 was isolated.

Methyl(4S)-6-(bromomethyl)-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate114a was prepared in analogy to compound C with procedures shown inExample 1 by using 3,4-difluoro-benzaldehyde instead of and2-chloro-4-fluoro-benzaldehyde.

Example 115 was prepared in analogy to Example 86 starting from 86k (22mg) and methyl(4S)-6-(bromomethyl)-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate114a (50 mg). 8 mg of Example 115 was isolated.

Examples 116 and 1172-[(3R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(3S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

The title compounds were prepared in analogy to Example 86 starting from(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 225 mg) and ethyl2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a(120 mg). The crude product was purified by preparative HPLC first, andthen chiral SFC, to afford Example 116 and Example 117.

Ethyl 2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate116a

Step I: To a solution of compound 86a (6.9 g, 20 mmol, 1.0 eq) in MeOH(100 mL) was added NaBH₄ (1.5 g, 40 mmol, 2.0 eq) slowly at roomtemperature, then the mixture was stirred at room temperature for 1 h.The mixture was quenched with water (100 mL), extracted with EA (100 mL)two times. The organic layer was combined, dried over Na₂SO₄ andconcentrated to give8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ol116b as a colorless oil, 6.24 g, yield: 90%. MS: calc'd (MH⁺) 348,measured (MH⁺) 348.

Step II: A mixture of compound 116b (6.24 g, 18 mmol, 1.0 eq) and TEA(9.2 g, 9 mmol, 5.0 eq) in DCM (100 mL) was added AcCl (4.2 g, 54 mmol)slowly and then stirred at room temperature for 2 h. The mixture wasquenched with water (100 mL), extracted with DCM (100 mL), the organiclayer was combined, dried over Na₂SO₄ and concentrated to give[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-yl]acetate116c as a colorless oil, 6.66 g, yield: 95%. MS: calc'd (MH⁺) 390,measured (MH⁺) 390.

Step III: A solution of compound 116c (6.24 g, 16 mmol, 1.0 eq) and TBAF(6.26 g, 24 mmol, 1.5 eq) in THF (100 mL) was stirred at 70° C. for 20h. The mixture was diluted with EA (100 mL), and washed with water (100mL) two times. The organic layer was extracted with 1N HCl (100 mL), theaqueous layer was adjust to PH=8 with NaHCO₃, extracted with DCM (100mL) two times, the DCM layer was dried over Na₂SO₄ and concentrated togive (8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-yl) acetate 116d asa colorless oil, 4.4 g, crude yield: 100%. MS: calc'd (MH⁺) 276,measured (MH⁺) 276.

Step IV: To a mixture of compound 116d (4.4 g, 16 mmol, 1.0 eq) in DCM(50 mL) was added DMP (13.6 g, 32 mmol, 2.0 eq) slowly at 0° C., thenthe mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with water, the solid was filtered off, thefiltrate was diluted with DCM (100 mL), washed with NaHCO₃ (100 mL)three times and brine (100 mL). The organic layer was dried over Na₂SO₄and concentrated. The residue was purified by silica gel (EA/PE=1:3) togive (8-benzyl-6-oxo-8-azabicyclo[3.2.1]octan-3-yl) acetate 116e as acolorless oil. 2.2 g, two step yield: 50%. MS: calc'd (MH⁺) 274,measured (MH⁺) 274.

Step V: A mixture of ketone 116e (2.2 g, 8 mmol, 1.0 eq) and DAST (6.44g, 40 mmol, 5.0 eq) in DCM (15 mL) was stirred at 60° C. in sealed tubefor 18 h. The mixture was added dropwise to a cooled aqueous NaHCO₃ (50mL, 5%) solution, then the mixture was extracted with EA (50 mL) twotimes, the organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel (EA/PE=1:3) to give(8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl) acetate 116f as aslight yellow oil. 1.48 g, yield: 50%. MS: calc'd (MH⁺) 296, measured(MH⁺) 296.

Step VI: A solution of compound 116f (1.48 g, 4 mmol, 1.0 eq) and K₂CO₃(1.1 g, 8 mmol, 2.0 eq) in MeOH (20 mL) was stirred at room temperaturefor 16 h. The mixture was quenched with water (100 mL), extracted withEA (100 mL) two times, the organic layer was combined, dried over Na₂SO₄and concentrated to give8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-ol 116g as a colorlessoil, 1.02 g, crude yield: 100° A. MS: calc'd (MH⁺) 254, measured (MH⁺)254.

Step VII: To a mixture of compound 116g (1.02 g, 4 mmol, 1.0 eq) in DCM(20 mL) was added DMP (3.4 g, 8 mmol, 2.0 eq) slowly at 0° C., then themixture was stirred at room temperature for 16 h. The reaction mixturewas quenched with water, the solid was filtered off, the filtrate wasdiluted with DCM (100 mL), washed with NaHCO₃ (100 mL) three times andbrine (100 mL). The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel (EA/PE=1:4) to give8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-one 116h as a colorlessoil. 0.5 g. MS: calc'd (MH⁺) 252, measured (MH⁺) 2520.

Step VIII: To a solution of diisopropylamine (1.02 g, 10 mmol, 5.0 eq)in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50°C. After 30 min, dry EA (880 mg, 10 mmol, 5.0 eq) in NMP/THF (11 mL,1:10) was added dropwise. After 1 h at −50° C., a solution of compound116h (500 mg, 2 mmol, 1.0 eq) in THF (5 mL) was added slowly, and theresulting mixture was warmed from −50° C. to room temperature for 2 h.The reaction mixture was quenched with water (50 mL), extracted with EA(100 mL). The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel (EA/PE=1:3) to give ethyl2-(8-benzyl-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate116i as a colorless oil. 490 mg, yield: 72%. ¹H NMR (400 MHz, DMSO-d6)ppm 7.37-7.19 (m, 5H), 4.45 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.84-3.70(m, 2H), 3.27 (d, J=5.0 Hz, 1H), 3.08 (d, J=11.3 Hz, 1H), 2.70 (q,J=13.6 Hz, 1H), 2.43 (s, 2H), 2.37-2.26 (m, 1H), 2.13-2.00 (m, 2H),1.84-1.72 (m, 1H), 1.52 (d, J=14.3 Hz, 1H), 1.22 (t, J=7.0 Hz, 3H); MS:calc'd (MH⁺) 340, measured (MH⁺) 340.

Step VIIII: A mixture of compound 116i (340 mg, 1 mmol, 1.0 eq) andPd(OH)₂/C (100 mg, 30%) in MeOH (20 mL) was stirred at room temperaturefor 16 h under 1 atmosphere of hydrogen. The mixture was filtered, andthe filtrate was concentrated to give ethyl2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a asa colorless oil, 224 mg, yield: 90%. MS: calc'd (MH⁺) 250, measured(MH⁺) 250.

Examples 118 and 1192-[(3R)-8-[[(4R)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(3S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

The title compounds were prepared in analogy to Example 86 starting frommethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate111a (220 mg) and ethyl2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a(120 mg). The crude product was purified by preparative HPLC first, andthen chiral SFC, to give Example 118 (20 mg) and Example 119 (15 mg).

Examples 120 and 1212-[(3R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid and2-[(3S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid

The title compounds were prepared in analogy to Example 86 starting frommethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate88a (220 mg) and ethyl2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a(120 mg). The crude product was purified by preparative HPLC first, andthen chiral SFC, to give Example 120 (30 mg) and Example 121 (30 mg).

Example 122 Methyl(4R)-6-[(3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

To a solution of methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 80 mg, 0.13 mmol) in dimethylformamide (3.0 mL) was addedcompound tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (28 mg,0.13 mmol) and potassium carbonate (40 mg, 0.29 mmol). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas poured into ice-water, extracted with EA (20 mL) three times. Thecombined organic phase was concentrated to give a crude tert-butyl8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(80 mg).

A mixture of tert-butyl8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(80 mg), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL) wasstirred at room temperature for one hour, and then concentrated. Theresidue was dissolved in dichloromethane (5.0 mL), followed by addingdiisopropylethylamine (0.2 mL) and acetic chloride (0.1 mL). The resultmixture was stirred at room temperature overnight. The reaction mixturewas concentrated and purified by prep-HPLC to give Methyl(4R)-6-[(3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate122 (11.3 mg).

Examples 123 and 1242-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compounds were prepared in analogy to Example 1 with ethyl2-(6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 123a and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C). The crude product from the final step was purified bypreparative HPLC to give two compounds, Example 123, and Example 124.

Preparation of ethyl2-(6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 123a

Step I: To a suspension of sodium hydride (396 mg, 60% dispersion inmineral oil, 9.9 mmol) in dry THF (5 ml) was added2-diethoxyphosphorylacetic acid ethyl ester (2.40 g, 10.8 mmol) at 0° C.The resulting mixture was stirred at room temperature for 10 mins, andthen heated at 80° C. for 20 mins. The reaction mixture was cooled downto room temperature. To the reaction mixture was added a solution oftert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.00 g,8.3 mmol) in dry THF (20 ml). The resulting mixture was stirred at 80°C. overnight. The solvent was removed and the residue was partitionedbetween ethyl acetate and water. The organic phase was dried,concentrated and purified by silica gel chromatography to givetert-butyl7-(2-ethoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate123b (1.20 g, 46.5%) and tert-butyl7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate123e (0.800 g, 30.8%). Compound 123b: ¹H NMR (400 MHz, CDCl₃):d=5.72-5.66 (m, 1H), 4.29-4.23 (m, 1H), 4.15 (d, J=7.3 Hz, 3H),4.05-3.97 (m, 1H), 3.88-3.77 (m, 2H), 3.76-3.65 (m, 2H), 2.77-2.61 (m,1H), 2.38 (d, J=15.3 Hz, 2H), 1.53-1.48 (m, 9H), 1.30-1.26 (m, 3H).

Step II: To a solution of tert-butyl hydroperoxide in 1,2-dichloroethane(8.0 mL, v/v 1:5, pre-dried over Na₂SO₄) was added compound 123b (600mg, 2.0 mmol) and selenium dioxide (220 mg, 2.0 mmol). The reactionmixture was sealed and heated to 70° C. under microwave for one hour.The reaction mixture was cooled down to room temperature, washed withsaturated Na₂SO₃ solution, and extracted with DCM (30 mL) three times.The organic phases were combined and dried over Na₂SO₄. After filtrationand concentration, the residue was purified by silica gel column to givetert-butyl(7E/Z)-7-(2-ethoxy-2-oxo-ethylidene)-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate123c (563 mg, yield: 90%). ¹H NMR (400 MHz, CDCl₃): d=5.83-5.44 (m, 1H),4.36-4.08 (m, 5H), 3.93-3.55 (m, 5H), 3.13-3.05 (m, 0.5H), 2.82-2.74 (m,0.5H), 2.30-2.22 (m, 0.5H), 2.10-2.03 (m, 0.5H), 1.53-1.49 (m, 9H),1.30-1.26 (m, 3H).

Step III: To a solution of compound 123c (18 g, 55 mmol) in ethanol (200mL) was added palladium hydroxide (3.0 g). The reaction mixture wasstirred at 40° C. overnight under 1 atm H₂. The reaction mixture wasfiltrated and concentrated to give tert-butyl7-(2-ethoxy-2-oxo-ethyl)-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate123d (18 g, crude). ¹H NMR (400 MHz, CDCl3): d=4.24-3.98 (m, 4H),3.90-3.78 (m, 1H), 3.70-3.48 (m, 4H), 2.79 (dd, J=5.3, 15.6 Hz, 0.5H),2.59 (d, J=7.0 Hz, 0.5H), 2.41 (dd, J=5.5, 15.8 Hz, 0.5H), 2.30 (dd,J=8.2, 15.7 Hz, 0.5H), 2.25-2.16 (m, 1H), 1.77-1.64 (m, 1H), 1.54-1.50(m, 9H), 1.42-1.26 (m, 5H).

Step IV: To a solution of compound 123d (100 mg) in dichloromethane (2.0mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture wasstirred at room temperature for one hour, and concentrated under reducedpressure to give ethyl2-(6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 123a, which wasused directly in next step without purification.

Examples 125 and 1262-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(78)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

Preparation of Examples 125 and 126

Example 125 was prepared in analogy to Example 86 starting from methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C) and 125a (one of the two enantiomers of ethyl2-endo-[6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate).

Example 126 was prepared in analogy to Example 86 starting from methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C) and 126a (the other enantiomer of ethyl2-endo-[6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate).

Preparation of the two enantiomers of ethyl2-endo-[6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate, 125aand 126a

Step I: To a solution of compound 123d (960 mg, 3.0 mmol) indichloromethane (30 mL) was added Dess-Martin reagent (2.54 g, 6.0 mmol)at 40° C. The reaction mixture was stirred for three hours, then anotherbatch of Dess-Martin reagent (1.27 g, 3.0 mmol) was added. The reactionmixture was stirred overnight. The reaction mixture was poured intoice-water, and filtrated. The filtrate was washed with sodiumbicarbonate solution and sodium sulphite solution, extracted withdichloromethane (50 mL) three times. The organic phase was dried overNa₂SO₄, and concentrated. The residue was purified by silica gel columnto give tert-butyl7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate125b (780 mg, yield: 80%).

Step II and III: a mixture of tert-butyl7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate125b (654 mg, 2.0 mmol), trifluoroacetic acid (1.0 mL) anddichloromethane (2.0 mL) was stirred at room temperature for one hour.The reaction mixture was concentrated. The residue was dissolved indimethylformamide (5.0 mL), followed by adding potassium carbonate (700mg, 5.0 mmol) and N,N-diisopropylethylamine (0.3 mL). The result mixturewas warmed to 40° C., then added dropwise benzyl chloroformate (311 μL,2.2 mmol) in dimethylformamide (1.0 mL). The resulting mixture wasstirred for another two hours. The reaction was quenched by addingice-water, extracted with PE: EA=5:1 (30 mL) three times. The combinedorganic phases were dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel column to give benzyl7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate125d (650 mg, yield: 90%).

Step IV: To a solution of benzyl7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate125d (14.4 g, 40 mmol) in dichloromethane (84 mL) was addeddiethylaminosulfur trifluoride (42 mL, 320 mmol). The reaction mixturewas stirred at 65° C. overnight. The reaction mixture was cooled downand diluted with ethyl acetate (300 mL). The mixture was poured intoice-water and sodium bicarbonate solution at 0° C. The reaction mixturewas extracted with PE: EA=5:1 (150 mL) three times. The combined organicphases were dried over Na₂SO₄, filtrated and concentrated. The residuewas purified by silica gel column (18% EA in petroleum ether),preparative HPLC, and then chiral SFC (OJ-H, 30*250 mm, 5 um, 5%isopropanol) to give a pair of enantiomers of benzyl7-endo-(2-ethoxy-2-oxo-ethyl)-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate,125e (2.0 g, peak 1) and 125f (3 g, peak 2).

Step V: To a solution of 125e (2.0 g, 5.22 mmol) in ethanol (25 mL) wasadded palladium hydroxide (1.0 g). The reaction mixture was stirred atroom temperature overnight, and then diluted with ethyl acetate (300mL). The mixture was filtrated and concentrated to give 125a, one of thetwo enantiomers of ethyl2-endo-[6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate (1.0 g,crude).

The other enantiomer of ethyl2-endo-[6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate, 126a,was prepared from 125f in analogy to compound 125a.

Examples 127 and 1282-[(7R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(7S)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

Preparation of Examples 127 and 128

Example 127 was prepared in analogy to Example 86 starting from ethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate127a and 125a. Compound 127a was prepared in analogy to methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C) in Example 1, by using ethyl acetoacetate and3,4-difluoro-2-methyl-benzaldehyde instead of methyl acetoacetate and2-chloro-4-fluoro-benzaldehyde, respectively.

Example 128 was prepared in analogy to Example 86 starting from ethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate127a and 126a.

Examples 129 and 1302-[(7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid and2-[(7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

Preparation of Examples 129 and 130

Example 129 was prepared in analogy to Example 86 starting from ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a and 125a.

Example 130 was prepared in analogy to Example 86 starting from ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a and 126a.

Example 1312-[(1R,5R,78)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid or2-[(1S,5S,7R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 86 starting frommethyl(4R)-6-(bromomethyl)-4-(2-chloro-3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate131a and 126a.

Methyl(4R)-6-(bromomethyl)-4-(2-chloro-3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate131a was prepared in analogy to methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C) in Example 1, by using 2-chloro-3,4-difluoro-benzaldehydeinstead of 2-chloro-4-fluoro-benzaldehyde.

Example 1322-[(1R,5R,78)-9-[[(48)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid or2-[(1S,5S,7R)-9-[[(48)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 86 starting frommethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate111a and 126a.

Example 133 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The titled compound was prepared by following procedure. To a solutionof methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 0.089 g, 0.20 mmol) and tert-butyl6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate 133a (0.096 g)in CH₂Cl₂ (3 ml) was added DIPEA (0.2 ml, 1.14 mmol) at roomtemperature. The resulting mixture was stirred at room temperatureovernight. The mixture was concentrated, and the residue (0.120 g, MS:calc'd (MH⁺) 606, measured (MH⁺) 606) was dissolved in dichloromethane(3 ml). To it was added trifluoroacetic acid (2 ml) at room temperature.The resulting mixture was stirred at room temperature for 2 hours. Thenthe mixture was concentrated and the residue was purified by preparativeHPLC to give the title compound (10 mg).

Preparation of tert-butyl6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate 133a

Step I: To a solution of tert-butyl3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.500 g, 2.2 mmol) indichloromethane (5 ml) was added triethylamine (0.443 g, 4.4 mmol) atroom temperature. The mixture was stirred at room temperature for a fewmins, and then benzyl chloroformate (0.751 g, 4.4 mmol) was added to thereaction mixture. The resulting mixture was stirred at room temperatureovernight. The mixture was partitioned between dichloromethane andwater. The organic phase was dried, and concentrated. The residue waspurified by silica gel chromatography to give 9-benzyl 7-tert-butyl3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133b (0.637 g,80.0%). MS: calc'd (MH⁺) 363, measured (MH⁺) 363.

Step II: A solution of 133b (0.100 g, 0.28 mmol) in ethyl acetate (1 ml)was added to a mixture of 10% NaIO₄ aqueous solution (0.283 mg in 3 mlH₂O) and RuO₂. The mixture was stirred at room temperature overnight.The organic phase was separated and the aqueous phase was extracted withethyl acetate (10 ml) two times. The combined organic phases weretreated with isopropyl alcohol (2 ml) to decompose RuO₄ oxidant, thenwashed three times with H₂O (5 ml), dried, and concentrated. The crudeproduct 9-benzyl-7-tert-butyl6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133c (0.150g) was used directly in next step. MS: calc'd (MH⁺) 377, measured (MH⁺)377.

Step III: A mixture of 133c (150 mg, 0.40 mmol) and Pd/C (20 mg) in MeOH(5 ml) was stirred under H₂ balloon at room temperature overnight. Thereaction mixture was filtered and the filtrate was concentrated to givecrude tert-butyl 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate133a (96 mg), which was used directly in next step. MS: calc'd (MH⁺)243, measured (MH⁺) 243.

Example 134Endo-2-[9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

To a stirred solution of(4R)-6-(bromomethyl)-4-(2-bromophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate134a (122 mg) and endo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid(PharmaBlock (Nanjing) R&D Co. Ltd, PBN20121752, 72 mg) in CH₂Cl₂ (3 ml)was added DIPEA (0.20 ml, 1.14 mmol) at room temperature. The resultingmixture was stirred at room temperature overnight. Then the reactionmixture was concentrated and the residue was purified by prep-HPLC togive the title compound (23 mg).(4R)-6-(bromomethyl)-4-(2-bromophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate134a was prepared in analogy to compound C in Example 1 by using2-bromoaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.

Example 135Endo-2-[9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 134, starting frommethyl(4R)-6-(bromomethyl)-4-(2-chloro-3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate131a (200 mg) and endo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid(PharmaBlock (Nanjing) R&D Co. Ltd, PBN20121752, 120 mg). 115 mg of thetitle compound was isolated.

Example 136Endo-2-[9-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid

The title compound was prepared in analogy to Example 134, starting frommethyl(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate96a (50 mg) and endo-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid(PharmaBlock (Nanjing) R&D Co. Ltd, PBN20121752, 40 mg). 10 mg of thetitle compound was isolated.

Example 137 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 134, starting frommethyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 58 mg) and ethyl2-hydroxy-2-(7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 137a(96 mg). 7 mg of the title compound was isolated.

Preparation of2-hydroxy-2-(7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 137a

Step I: To a mixture of tert-butyl7-(2-ethoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate123b (0.800 g, 2.6 mmol) in acetone (8 ml) and water (2 ml) were addedN-methylmorpholine-N-oxide (0.903 g, 7.7 mmol) and Osmium tetroxidesolution (0.3 ml, 4 wt % in H₂O, 1.2 mmol) at room temperature. Theresulting mixture was stirred at room temperature overnight. The mixturewas then concentrated and the crude diol 137b (0.950 g) was useddirectly in next step without further purification.

Step II: To a solution of diol 137b (150 mg, 0.43 mmol) indichloromethane (2 ml) was added trifluoroacetic acid (2 ml) at roomtemperature. The resulting mixture was stirred at room temperature for 2hours, then concentrated to give2-hydroxy-2-(7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 137a(120 mg) as a crude product, which was used directly in next step.

Example 138 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 134, starting frommethyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 86 mg) and ethyl2-(6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 138a (142mg). 6 mg of the title compound was isolated.

Preparation of ethyl2-(6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 138a

Step I: To a tert-butyl7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate123e (0.800 g, 2.6 mmol) in acetone (8 ml) and water (2 ml) were addedN-methylmorpholine-N-oxide (0.903 g, 7.7 mmol) and Osmium tetroxidesolution (0.3 ml, 4 wt % in H2O, 1.2 mmol) at room temperature. Theresulting mixture was stirred at room temperature overnight. The mixturewas then concentrated to give crude diol 138b (0.900 g), which was useddirectly in next step without further purification. MS: calc'd (MH⁺)346, measured (MH⁺) 346.

Step II: To a solution of diol 138b (200 mg, 0.58 mmol) indichloromethane (2 ml) was added trifluoroacetic acid (2 ml) at roomtemperature. The resulting mixture was stirred at room temperature for 2hours, then concentrated to give 142 mg of ethyl2-(6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 138a, whichwas used directly in next step. MS: calc'd (MH⁺) 246, measured (MH⁺)246.

Example 1397-amino-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared in analogy to Example 133 by using7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139a (40 mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 39 mg). 4 mg of the title compound was isolated.

Preparation of7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139a

Step I: A mixture of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.9g, 3.9 mmol), KCN (760 mg, 11.7 mmol), and (NH₄)₂CO₃ (1.1 g, 11.7 mmol)in EtOH (8 ml) and H₂O (8 ml) was stirred at 55° C. for 2 days. Then themixture was poured into water (100 ml) and extracted with DCM (100 ml)two times. The organic layer was dried and concentrated to obtain aresidue. The residue was purified by chromatography on silica gel(PE/EA=1:1 then DCM/MeOH=15:1) to give9-benzylspiro[3-oxa-9-azabicyclo[3.3.1]nonane-7,5′-imidazolidine]-2′,4′-dione139b (0.6 g, 70%) as white solid. MS: calc'd (MH⁺) 302, measured (MH⁺)302.

Step II: LiOH (240 mg, 10 mmol) was added to a suspension of compound139 b (0.3 g, 1 mmol) in H₂O (30 ml). The result mixture was stirred at100° C. for 40 h. The mixture was cooled to room temperature andfiltered to remove a white solid, and the filtrate was evaporated. ThepH of the concentrate was adjusted from 12 to 5 with concentrated HCl,and the solution was evaporated to dryness. The residue was treated withmethanol to lead to a suspension. After filtration and being washed withCH₃OH, the solid was dried to give7-amino-9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid 139c(200 mg, 72%) as white solid. MS: calc'd (MH⁺) 277, measured (MH⁺) 277.

Step III: NaOH (45 mg, 1.1 mmol) was added to a mixture of compound 139c(100 mg, 0.36 mmol) and (Boc)₂O (457 mg, 0.72 mmol) in THF (15 ml) andH₂O (15 ml). The mixture was stirred at 70° C. overnight. The THF wasevaporated and the water solution was acidified with 1N HCl until pH=5.The water solution was extracted with EA (3×50 ml). The organic layerwas dried and concentrated to give a residue. The residue was purifiedby pre-HPLC to afford9-benzyl-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139d (50 mg, 37%) as white solid. MS: calc'd (MH⁺) 377, measured(MH⁺) 377; ¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 2.30-2.33 (m, 2H),2.50-2.55 (m, 2H), 3.02-3.04 (d, 2H), 3.69-3.72 (d, 2H), 4.12-4.22 (m,4H), 7.35-7.41 (m, 3H), 7.47-7.49 (d, 2H).

Step IV: A mixture of compound 139d (0.050 g, 0.13 mmol) and Pd/C (20mg) in MeOH (5 ml) was stirred under H₂ balloon at room temperatureovernight. The mixture was filtered and the filtrate was concentrated togive 40 mg of the crude7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139a, which was used directly in next step without furtherpurification. MS: calc'd (MH⁺) 287, measured (MH⁺) 287.

Example 1407-amino-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared in analogy to Example 133 by using7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139a (49 mg) and ethyl(4R)-6-(bromomethyl)-4-(2,3-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate140a (48 mg). 5 mg of the title compound was isolated.

Ethyl(4R)-6-(bromomethyl)-4-(2,3-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate140a was prepared in analogy to compound C in Example 1 by using ethylacetoacetate and 2,3-difluorobenzaldehyde instead of methyl acetoacetateand 2-chloro-4-fluoro-benzaldehyde, respectively.

Example 1417-amino-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared in analogy to Example 133 by using7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid 139a (49 mg) and ethyl(4R)-6-(bromomethyl)-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate70a (55 mg). 15 mg of the title compound was isolated.

Example 142 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1a in Example 1 byusing methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 200 mg) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride(100 mg). 44 mg of title compound was isolated.

Example 143 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1a in Example 1 byusing methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 50 mg) and 5,5-difluoro-2-azabicyclo[2.2.1]heptane (WuxiAppTec Co., Ltd, WX120101, 29 mg). 7 mg of title compound was isolated.

Example 144 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-3-azabicyclo[2.2.1]heptan-3-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1a in Example 1 byusing methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 50 mg) and 5,5-difluoro-3-azabicyclo[2.2.1]heptane (WuxiAppTec Co. Ltd, WX120379, 29 mg). 26 mg of title compound was isolated.

Example 145 Methyl(4R)-6-[[4-(acetamidomethyl)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1a in Example 1 byusing methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 65 mg) andN-(5-oxa-2-azabicyclo[2.2.1]heptan-4-ylmethyl)acetamide (37 mg). 5.5 mgof title compound was isolated.

Preparation of N-(5-oxa-2-azabicyclo[2.2.1]heptan-4-ylmethyl)acetamide

A mixture of tert-butyl4-(aminomethyl)-5-oxa-2-azabicyclo[2.2.1]heptane-2-carboxylate (WuxiAppTec, CAS 1357351-98-4) (50 mg, 0.22 mmol), TEA (44.4 mg, 0.44 mmol)in DCM (2 mL) was added CH₃CO₂Cl (26 mg, 0.33 mmol) at 0° C. After 2hours, the solvent was removed under reduced pressure. The residue wastreated with TFA in DCM. After stirring for 2 hours at room temperature,the residue was used in next step without purification. MS: calc'd (MH⁺)271, measured (MH⁺) 271.

Examples 146 and 147 Example 146 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Example 147 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-[(2,2,2-trifluoroacetyl)amino]-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 146 and Example 147

A mixture of ethyl2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate146a (0.1 g, 0.3 mmol) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylateC (90 mg, 0.2 mmol), DIPEA (77.4 mg, 0.6 mmol) in DCM (5 mL) was stirredfor 12 hours at room temperature. The mixture was concentrated to givecrude methyl(4R)-6-[[7-(tert-butoxycarbonylamino)-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate146b. MS: calc'd (MH⁺) 692, exp (MH⁺) 692.

A mixture of 146b (0.14 g, 0.20 mmol), TFA (2 mL) in DCM (5 mL) wasstirred for 2 hours. The solvents were removed under reduced pressure togive crude methyl(4R)-6-[[7-amino-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylatein TFA salt form. MS: calc'd (MH⁺) 592, exp (MH⁺) 592. This TFA salt (35mg, 0.051 mmol) was dissolved in a mixture of TEA (20.6 mg, 0.204 mmol)in DCM (3 mL). To it was added CH₃SO₂C1 (11.7 mg, 0.102 mmol). Theresulting mixture was stirred for 12 hours at room temperature, andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give two products, Example 146 and Example 147.

Preparation of ethyl2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate146a

Step I: The mixture of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one(0.5 g, 2.2 mmol), 3-methoxy-3-oxo-propanoic acid (0.44 g, 3.3 mmol),ammonium acetate (0.33 g, 4.4 mmol) in ethanol (5 mL) was refluxed for 3hours. After removal of solvent, the residue was purified by flashsilica gel chromatography to afford ethyl2-(7-amino-9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 146c.Yield: 5%. MS: calc'd (MH⁺) 319, measured (MH⁺) 319.

Step II: A mixture of ethyl2-(7-amino-9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate (1.2 g,3.8 mmol), (Boc)₂O (1.23 g, 5.7 mmol), and TEA (0.77 g, 7.6 mmol) in DCM(15 mL) was stirred for 2 hours at room temperature. After removal ofsolvent, the residue was purified by flash silica gel chromatography toafford ethyl2-[9-benzyl-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate146d as an oil, 1.5 g, yield, 95%. MS: calc'd (MH⁺) 419, measured (MH⁺)419.

Step III: A mixture of ethyl2-[9-benzyl-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate(0.7 g, 1.67 mmol), 10% Pd/C (0.5 g) in methanol (20 mL) was stirred for12 hours under 1 atm H₂. Filtration followed by removal of the residuegave ethyl2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate146a, which was used in next step without purification. Yield: 96%. MS:calc'd (MH⁺) 329, measured (MH⁺) 329.

Examples 148 and 149(1S,4R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid and(1R,4S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid

The title compounds were prepared in analogy to Example 1 by usingmethyl 2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylate 148a (22mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 106 mg). Final purification by preparative HPLC affordedtwo products, Example 148 and example 149.

Preparation of methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylate 148a

Step I: A mixture of O7-tert-butyl O4-methyl2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (prepared accordingto the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.34g, 1.27 mmol), TFA (1.5 ml) in DCM was stirred for 2 hours. Afterremoval of solvent and TFA under reduced pressure, the residue wasdissolved into DCM (5 mL). To it was added TEA (0.51 g, 5.08 mmol) andCbzCl (0.43 g, 2.54 mmol). After 12 hours, the mixture was concentratedunder reduced pressure. The residue was purified by flash chromatographyto give O7-benzyl O4-methyl2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate 148b. Yield:30%. MS:calc'd (MH⁺) 304, measured (MH⁺) 304.

Step II: A mixture of O7-benzyl O4-methyl2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (0.5 g, 1.65 mmol)and DAST (2.66 g, 16.5 mmol) in DCM (2 mL) was heated for 12 hours at45° C., then quenched with water, extracted with DCM, washed with NaHCO₃(aq), After removal of solvent, the residue was purified by flashchromatography to give O7-benzyl O4-methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate 148c,Yield:8%. MS: calc'd (MH⁺) 326, measured (MH⁺) 326.

Step III: The mixture of O7-benzyl O4-methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (0.24 g, 0.74mmol), 10% Pd/C (0.3 g) in methanol (20 mL) was stirred for 12 hoursunder 1 atm H2. Removal of the catalyst solid and solvent gave methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylate 148a. This crudeproduct was used in next step without purification. Yield: 69.3%. MS:calc'd (MH⁺) 192, measured (MH⁺) 192.

Example 1508-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared in analogy to Example 1, by using methyl6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a (200 mg) andethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate98a (400 mg). 30 mg of the title compound was isolated finally afterpreparative HPLC purification. Preparation of methyl6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a:

Step I: To a mixture of8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (1.2 g) and TosMIC(1.95 g) in a mixture of 20 mL of DME and 0.5 mL of absolute EtOH wasadded t-BuOK (3.5 g) portionwise while keeping the temperature between 5and 10° C. The resulting mixture was stirred at room temperature 30 min,and then warmed to 35-40° C. for another 30 minutes. The suspension thusobtained was cooled to room temperature, and the precipitate (TosK) wasremoved and extracted with DME. The combined DME solutions wereconcentrated to 3 mL and purified by silica gel chromatography to give8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octane-3-carbonitrile 150b (0.8g).

Step II: 0.8 g of nitrile 150b was dissolved in 10 ml of DCM. Then 3 eqof Dess-Martin reagent was added to the solution and stirred at roomtemperature overnight. The mixture was filtered and the filtrate wasconcentrated to give8-benzyl-6-oxo-8-azabicyclo[3.2.1]octane-3-carbonitrile 150c as a crudeproduct (0.9 g), which was used in the next step without furtherpurification.

Step III: 0.3 g of ketone 150c was dissolved in 1 ml of DCM. To it wasadded 0.5 ml of DAST. The resulting mixture was heated at 60° C.overnight, then concentrated. The residue was purified by silica gelchromatography to give 0.2 g of8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carbonitrile 150d asan oil. Step IV: 0.2 g of compound 150d was dissolved in 10 ml of 2 MHCl in methanol and heated at 80° C. overnight. After removal of thesolvent, the residue was purified by silica gel chromatography to givemethyl 8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate150e as an oil, 0.22 g.

Step V: A mixture of compound 150d (0.22 g) and Pd(OH)2 (25 mg) in 20 mlmethanol under 1 atm of H₂ was stirred at room temperature overnight.Removal of the solvent afforded methyl6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a (200 mg).

Examples 151 and 152(5S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylicacid(5R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylicacid

The title compounds were prepared in analogy to Example 1 by usingmethyl 2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylate 151a (150mg) and methyl(4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C, 520 mg) in the N-alkylation step. Purification of the finalproduct by preparative HPLC afforded Example 151 (2 mg) and Example 152(2 mg).

Preparation of methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylate 151a

Step I: A mixture of ethyl(5R)-2-acetoxy-7-azabicyclo[2.2.1]heptane-5-carboxylate 151b (preparedin analogy to O7-tert-butyl O4-methyl2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate starting from methyltrans-6-acetamidocyclohex-3-ene-1-carboxylate with procedures reportedin the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.55g, 2.4 mmol) in DCM (10 mL) and sodium carbonate (0.76 g, 7.2 mmol) inwater (3 mL) was added CbzCl (0.61 g, 3.6 mmol) dropwise. Afteraddition, the mixture was stirred for 2 hours, then extracted with DCM.Removal of solvent afforded O7-benzyl O5-methyl2-acetoxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151c, which wasused in next step without purification. Crude yield: 100%. MS: calc'd(MH⁺) 362, measured (MH⁺) 362.

Step II: A mixture of O7-benzyl O5-ethyl(5R)-2-acetoxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.87 g, 2.4mmol) and DBU (0.73 g, 4.8 mmol) in methanol (20 mL) was stirred for 12hours at room temperature. After removal of solvent, the residue waspurified by silica gel chromatography to give O7-benzyl O5-ethyl(5R)-2-hydroxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151d. Yield:45%. MS: calc'd (MH⁺) 306, measured (MH⁺) 306.

Step III: A mixture of O7-benzyl O5-ethyl(5R)-2-hydroxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.37 g, 1.1mmol), Dess-martin reagent (1.38 g, 3.3 mmol) in DCM (50 mL) was stirredfor 12 hours. After removal of solvent, the residue was purified bysilica gel chromatography to give O7-benzyl O5-ethyl(5R)-2-oxo-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151e. Yield:90%. MS: calc'd (MH⁺) 304, measured (MH⁺) 304.

Step III: A mixture of O7-benzyl O5-ethyl(5R)-2-oxo-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.4 g, 1.32mmol), DAST (2.13 g, 13.2 mmol) in DCM (2 mL) was stirred for 12 hoursat 50° C., then quenched with water, extracted with DCM. After removalof solvent, the residue was purified by silica gel chromatography togive O7-benzyl O5-ethyl(5R)-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151f.Yield: 38%. MS: calc'd (MH⁺) 326, measured (MH⁺) 326.

Step IV: A mixture of O7-benzyl O5-ethyl(5R)-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.33 g,1.0 mmol), 10% Pd/C (0.4 g) in methanol (20 mL) was stirred for 24 hoursat 1 atm of H₂. Removal of catalyst and solvent afforded crude methyl2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylate 151a, which wasused in next step without purification. Yield: 100%. MS: calc'd (MH⁺)192, measured (MH⁺) 192.

Example 153 HBV Inhibition Assays

Cell Lines and Culture Conditions:

HepG2.2.15 and HepDE19 are stably-transfected cell lines containing theHBV genome. Both cell lines are derived from the hepatoblastoma cellline Hep G2 (American Type Culture Collection, ATCC® HB-8065™) by thepublished procedures described in references: MA Selles et al. Proc.Natl. Acad. Sci. USA 1987, 84, 1005-1009 and H Guo et al. Journal ofVirology 2007, 81, 12472-12484, respectively. Both cell lines weremaintained in Dulbecco's modified Eagle's medium (DMEM)-F12 mediumsupplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mLstreptomycin, and 0.5 mg/mL of G418.

While HepG2.2.15 cells constitutively support HBV replication andproduction of virus particles, HepDE19 cells are inducible bytetracycline. Addition of 1 μg/mL tetracycline in culture mediumsuppresses HBV replication in HepDE19 cells, whereas switching totetracycline-free medium resumes this process.

Anti-HBV Activity In Vitro:

HepG2.2.15 cells were seeded into 96-well plates (3×10⁴ cells in 100 μLmedia per well) and incubated overnight at 37° C. The test compoundswere serially half-log diluted in DMSO, then diluted 100 times inculture media. 100 μL diluted compounds were added into the plates toreach 0.5% final concentration of DMSO in every well. Five days aftercompound treatment, culture supernatant was collected for furtheranalysis.

For quantitative PCR detection of extracellular HBV DNA, 100 μL culturesupernatant was collected and processed in MagNA Pure 96 Nucleic AcidPurification System (Roche Applied Science) for viral DNA extraction.The extracted samples were subjected to HBV DNA quantification by qPCR.The effective compound concentration at which HBV replication isinhibited by 50% (EC₅₀) was determined.

The Examples were tested in the above assays as described herein andfound to have EC₅₀<1 μM in HepG2.2.15 assay. Particular compounds offormula I were found to have EC₅₀<0.1 μM in HepG2.2.15 assay (See Table2).

Cytotoxicity and Selectivity Indexes:

In a cell culture model, apparent antiviral activity of a compound canbe the result of host cell death after exposure to the compound. Todetermine whether the anti-HBV effect of a test compound is due tocytotoxicity, HepDE19 cells were seeded into 96-well plates (5×10³ cellsper well) and treated with compounds as described above for EC₅₀determination. Five days after treatment, cell viability was measured byaddition of 20 μL of CCK-8 reagent. Two hours after incubation at 37°C., the absorbance at wavelengths of 450 nm and 630 nm (0D₄₅₀ and OD₆₃₀)was recorded by a plate reader. The concentration results in the deathof 50% of the host cells (CC₅₀) of each compound was determined (SeeTable 5).

Based on CC₅₀ and EC₅₀ data, selectivity indexes were determined asshown in Table 5.

Example 154 Human Microsomal Clearance Assay

Microsomes were preincubated with test compound for 10 minutes at 37° C.in 100 mM phosphate buffer with pH 7.4. The reactions were initiated byadding NADPH regenerating system to give a final incubation volume of400 μL. The incubations finally contained 1 μM test compound, 0.5 mg/mLliver microsomal protein, 3.0 mM glucose 6-phosphate, 1.0 mM NADP, 3.0mM MgCl₂ and 0.05 mg/mL glucose 6-phosphate dehydrogenase in 100 mMphosphate buffer with pH 7.4. After incubation times of 0, 3, 6, 9, 15and 30 minutes, 50 μL, incubation was transferred to the quench solutioncontaining the internal standard which was 2 μM tolbutamide. Afterprecipitation and centrifugation, test compound concentrations in thesamples were determined by LC-MS/MS. Controls of no NADPH regeneratingsystem at zero and 30 minutes were also prepared and analyzed.

Results of human microsomal clearance data of particular compounds aregiven in Table 3.

Example 155 LYSA Description

Samples are prepared in duplicate from 10 mM DMSO stock solutions. Afterevaporation of DMSO with a centrifugal vacuum evaporator, the residue issolved in 0.05 M phosphate buffer (pH 6.5), stirred for one hour andthen shook for two hours. After one night, the solution is filteredusing a microtiter filter plate and then the filtrate and its 1/10dilution are then analyzed by direct UV measurement or by HPLC-UV. Inaddition a four-point calibration curve is prepared from the 10 mM stocksolutions and used for the solubility determination of the compounds.The results are in μg/ml. In case the percentage of sample measured insolution after evaporation divided by the calculated maximum of sampleamount is bigger than 80% the solubility is reported as bigger than thisvalue.

Results of Lysa are given in Table 4.

Example 156 Cytochrome P450 (Cyp450) Induction Screening Assay

Materials

Cell Culture

Human cryopreserved hepatocytes (Life Technologies, Carlsbad, USA) werethawed and cultured in collagen I coated 96-well plates with a densityof 52,000 cells/well. After attachment, medium was changed and cellswere pre-cultured overnight in hepatocyte maintenance medium (HMM;Lonza, Switzerland).

Test compounds were dosed to the cells next morning at an indicatedconcentration (up to 10 μM) in HMM culture media containing gentamycinand a constant 0.1% DMSO. Similarly, dilutions of the positive inducercompounds omeprazole (prototypical inducer of human CYP1A2; finalconcentrations: 1 and 10 μM), phenobarbital (prototypical inducer ofhuman CYP2B6; final concentrations: 100 and 1000 μM) and rifampicin(prototypical inducer of human CYP3A4; final concentrations: 1 and 10μM) were prepared from 1000 fold DMSO stock solutions in HMM containinggentamycin. Medium change was then performed and cells were exposed for24 hours to test compounds, positive inducer compounds, or vehicle (0.1%DMSO), respectively.

At the end of the compound exposure period, medium was removed and cellslysed using 100 μL/well MagNA Pure LC RNA isolation tissue lysis buffer(Roche Diagnostics AG, Rotkreuz, Switzerland). Plates were then sealedand frozen at −80° C. until further workup.

mRNA Isolation, Processing and qRT-PCR

mRNA isolation was performed using the MagNA Pure 96 system (RocheDiagnostics AG, Rotkreuz, Switzerland) and the respective cellular RNAlarge volume kit (Roche Diagnostics AG, Rotkreuz, Switzerland) fromthawed samples diluted 1:1 with PBS. The volume of the cell lysis and anelution volume of 100 μL were used. 20 μL of the resulting mRNAsuspension was then used for reverse transcription using 20 μL of thetranscript or first stand cDNA synthesis kit (Roche prime Supply,Mannheim, Germany). The resulting cDNA was diluted with 40 μL of H₂Obefore using for qRT-PCR. qRT-PCR was performed by using the forward andthe reverse primer, the corresponding UPL (all from Microsynth, Balgach,Switzerland) and the Taqman Fast advanced master mix (AppliedBiosystems), on an ABI 7900 machine (Applied Biosystems).

Calculations

qRT-PCR Ct-values for the respective P450s were put into relation to theCt-value of RN18S1 (microsynth, Balgach, Switzerland) of the samesample. Doing so, a respective Δct-value was calculated. Using theaverage of all Δct-values for the vehicle control samples, a ΔΔct-valuewas calculated for each sample(ΔΔct-value(sample)=Δct-value(sample)−average of Δct-value of allvehicle controls). The fold induction of the respective sample wascalculated as 2̂(−ΔΔct). The individual fold induction values were thenaveraged per treatment condition (usually n=3 biological replicates).

Relative induction values to the respective positive inducer compoundcondition (10 μM omeprazole for CYP1A2; 1000 μM Phenobarbital forCYP2B6; 10 μM rifampicin for CYP3A4) were then calculated from the foldinduction values as follows:

Relative induction(%)=100×(T−V)/(P−V)

T: fold induction of test compound condition

P: fold induction of positive inducer compound

V: fold induction of vehicle controls

Results of CYP3A4 induction are given in Table 6.

Example A

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch  25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg 425mg

Example B

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose 95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

1. A compounds of formula (I)

wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen or C₁₋₆alkyl; R³ is hydrogen or C₁₋₆alkyl;R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and the otherone is hydrogen, halogen or hydroxy; one of R^(5b) and R^(6b) ishydrogen or halogen, and the other one is hydrogen or halogen; R⁹ ishydrogen or carboxy; one of R¹⁷ and R¹⁸ is hydrogen, halogen, hydroxy,amino, C₁₋₆alkylsulfonylamino or trifluoromethylcarbonylamino, the otherone is hydrogen, halogen, hydroxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-O—,C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—O—,carboxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-NH—, C₁₋₆alkylsulfonyl-NH—,aminocarbonyl-NH— or aminosulfonyl-NH—; wherein —C_(y)H_(2y)— isunsubstituted once or more times substituted by hydroxy; or R^(6a) andR¹⁷ together with the carbon atoms, to which they are attached, form aring of isoxazolyl, pyrazolyl or oxo-dihydropyrazolyl, which ring isunsubstituted or once or more times substituted by C₁₋₆alkyl; or R¹⁷ andR¹⁸ together with the carbon atom, to which they are attached, formdiazirinyl; X is oxygen; sulfur; —N(carbonylC₁₋₆alkyl)-; or —C(R¹⁵R¹⁶)—,wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the other one ishydrogen or carboxy-C_(y)H_(2y)—; r is 0 or 1; m is 0 or 1; n is 0 or 1;y is 0-6; or R⁴ is

wherein R⁷ is hydrogen or halogen; R⁸ is hydrogen or halogen; R¹⁰ ishydrogen, halogen, hydroxy-C_(y)H_(2y)— orC₁₋₆alkylcarbonylamino-C_(y)H_(2y)—; R¹¹ is hydrogen or carboxy; R¹² ishydrogen or carboxy; W is a bond, oxygen, —CH₂—, —CF₂— or—N(carbonylC₁₋₆alkyl)-; t is 1 or 2; y is 0-6; with the proviso that

is excluded; or R⁴ is

wherein R¹⁹ is hydrogen; C₁₋₆alkyl, which is unsubstituted or once ormore times substituted by halogen; C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—;hydroxy-C_(y)H_(2y)-carbonyl; carboxy-C_(y)H_(2y)-carbonyl;C₁₋₆alkylaminosulfonyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl;aminocarbonyl; or aminosulfonyl; Y is carbonyl or —CH₂—; u is 0 or 1; yis 0-6; or R⁴ is

wherein M is a bond, —CH₂— or —N(R¹⁴)—CH₂—; R¹⁴ is C₁₋₆alkoxycarbonyl;or pharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 2. A compound according to claim1, wherein R¹ is methyl or ethyl; R² is phenyl, which is once or twiceor three times substituted by fluoro, chloro, bromo or methyl; R³ ishydrogen or methyl; R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and the otherone is hydrogen, fluoro or hydroxy; one of R^(5b) and R^(6b) is hydrogenor fluoro, and the other one is hydrogen or fluoro; R⁹ is hydrogen orcarboxy; one of R¹⁷ and R¹⁸ is hydrogen, fluoro, hydroxy, amino,methylsulfonylamino or trifluoromethylcarbonylamino, the other one ishydrogen, fluoro, hydroxy, hydroxymethyl, methylcarbonyl-O—,methoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,methoxycarbonyl(hydroxy)methyl, ethoxycarbonyl(hydroxy)methyl,carboxymethyl-O—, carboxy, carboxymethyl, methylcarbonylamino,aminocarbonylamino, methylsulfonylamino or aminosulfonylamino; or R^(6a)and R¹⁷ together with the carbon atoms, to which they are attached, forma ring of isoxazolyl, pyrazolyl or oxo-dihydropyrazolyl, which ring isunsubstituted or once or more times substituted by methyl; or R¹⁷ andR¹⁸ together with the carbon atom, to which they are attached, formdiazirinyl; X is oxygen; sulfur; —N(carbonylmethyl)-; or —C(R¹⁵R¹⁶)—,wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and the other one ishydrogen, carboxy or carboxymethyl; r is 0 or 1; m is 0 or 1; n is 0 or1; or R⁴ is

wherein R⁷ is hydrogen or fluoro; R⁸ is hydrogen or fluoro; R¹⁰ ishydrogen, fluoro, hydroxymethyl or methylcarbonylaminomethyl; R¹¹ ishydrogen or carboxy; R¹² is hydrogen or carboxy; W is a bond, oxygen,—CH₂—, —CF₂— or —N(carbonylmethyl)-; t is 1 or 2; with the proviso that

is excluded; or R⁴ is

wherein R¹⁹ is hydrogen, methyl, isopropyl, difluoromethylmethyl,methylcarbonyl, methoxycarbonyl, ethoxycarbonylisopropyl,hydroxymethylcarbonyl, carboxyisopropylcarbonyl, aminocarbonyl,methylsulfonyl, aminosulfonyl or methylaminosulfonyl; Y is carbonyl or—CH₂—; u is 0 or 1; or R⁴ is

wherein M is a bond, —CH₂— or —N(carbonyltert-butoxy)-CH₂—; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 3. A compound according to claim1, wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice orthree times substituted by halogen or C₁₋₆alkyl; R³ is hydrogen orC₁₋₆alkyl; R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and the otherone is hydrogen or halogen; R⁹ is hydrogen or carboxy; one of R¹⁷ andR¹⁸ is hydrogen or C₁₋₆alkylsulfonylamino, the other one is hydrogen,C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—O—,carboxy-C_(y)H_(2y)—, C₁₋₆alkylcarbonyl-NH—, C₁₋₆alkylsulfonyl-NH— oraminosulfonyl-NH—; or R^(6a) and R¹⁷ together with the carbon atoms, towhich they are attached, form pyrazolyl; X is oxygen; sulfur; or—C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and theother one is hydrogen or carboxy-C_(y)H_(2y)—; r is 0 or 1; m is 0 or 1;n is 0 or 1; y is 0-6; or pharmaceutically acceptable salts, ortautomerism isomers, or enantiomers, or diastereomers thereof.
 4. Acompound according to claim 1, wherein R¹ is methyl or ethyl; R² isphenyl, which is once or twice or three times substituted by fluoro,chloro, bromo or methyl; R³ is hydrogen or methyl; R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and the otherone is hydrogen or fluoro; R⁹ is hydrogen or carboxy; one of R¹⁷ and R¹⁸is hydrogen or methylsulfonylamino, the other one is hydrogen,ethoxycarbonylmethyl, carboxymethyl-O—, carboxy, carboxymethyl,methylcarbonyl-NH—, methylsulfonyl-NH— or aminosulfonyl-NH—; or R^(6a)and R¹⁷ together with the carbon atoms, to which they are attached, formpyrazolyl; X is oxygen; sulfur; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ andR¹⁶ is hydrogen or hydroxy, and the other one is hydrogen, carboxy orcarboxymethyl; r is 0 or 1; m is 0 or 1; n is 0 or 1; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 5. A compound of formula (IA)according to claim 1,

wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen or C₁₋₆alkyl; R³ is hydrogen or C₁₋₆alkyl;one of R^(5a) and R^(6a) is hydrogen or halogen, and the other one ishydrogen, halogen or hydroxy; R¹⁷ is hydrogen or amino; p is 0 or 1; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 6. A compound according to claim1, wherein R¹ is methyl or ethyl; R² is phenyl, which is once or twiceor three times substituted by fluoro, chloro, bromo or methyl; R³ ishydrogen or methyl; one of R^(5a) and R^(6a) is hydrogen or fluoro, andthe other one is hydrogen, fluoro or hydroxy; R¹⁷ is hydrogen or amino;p is 0 or 1; or pharmaceutically acceptable salts, or tautomerismisomers, or enantiomers, or diastereomers thereof.
 7. A compound offormula (IB) of claim 1,

wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen or C₁₋₆alkyl; R³ is hydrogen; R¹⁵ ishydrogen or hydroxy; q is 0 or 1; or pharmaceutically acceptable salts,or tautomerism isomers, or enantiomers, or diastereomers thereof.
 8. Acompound of claim 1, wherein R¹ is methyl or ethyl; R² is phenyl, whichis once or twice or three times substituted by fluoro, chloro, bromo ormethyl; R³ is hydrogen; R¹⁵ is hydrogen or hydroxy; q is 0 or 1; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 9. A compound of claim 1, whereinR¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or three timessubstituted by halogen; R³ is hydrogen; R⁴ is

wherein R¹⁹ is hydrogen, aminocarbonyl, aminosulfonyl orhydroxy-C_(y)H_(2y)-carbonyl; Y is —CH₂— or carbonyl; j is 0 or 1; y is0-6; or pharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 10. A compound of claim 1,wherein R¹ is methyl; R² is phenyl, which is once or twice or threetimes substituted by fluoro or chloro; R³ is hydrogen; R⁴ is

wherein R¹⁹ is hydrogen, aminocarbonyl, aminosulfonyl orhydroxymethylcarbonyl; Y is —CH₂— or carbonyl; j is 0 or 1; orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof.
 11. A compound of formula I,wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen; R³ is hydrogen; R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or halogen, and the otherone is hydrogen or halogen; R⁹ is hydrogen or carboxy; one of R¹⁷ andR¹⁸ is hydrogen, the other one is hydrogen or carboxy-C_(y)H_(2y)—; X isoxygen; or —C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is hydrogen orhydroxy, and the other one is hydrogen or carboxy-C_(y)H_(2y)—; r is 0or 1; m is 1; n is 0 or 1; y is 0-6; or a pharmaceutically acceptablesalt or tautomerism isomers or enantiomers or diastereomers thereof. 12.A compound of formula I, wherein R¹ is methyl or ethyl; R² is phenyl,which is once or twice or three times substituted by fluoro or chloro;R³ is hydrogen; R⁴ is

wherein one of R^(5a) and R^(6a) is hydrogen or fluoro, and the otherone is hydrogen or fluoro; R⁹ is hydrogen or carboxy; one of R¹⁷ and R¹⁸is hydrogen, the other one is hydrogen or carboxymethyl; X is oxygen; or—C(R¹⁵R¹⁶)—, wherein one of R¹⁵ and R¹⁶ is hydrogen or hydroxy, and theother one is hydrogen or carboxymethyl; r is 0 or 1; m is 1; n is 0 or1; or a pharmaceutically acceptable salt or tautomerism isomers orenantiomers or diastereomers thereof.
 13. A compound of formula (IC) ofclaim 1,

wherein R¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or threetimes substituted by halogen; R³ is hydrogen or C₁₋₆alkyl; R⁴ isselected from

wherein R¹⁰ is hydroxy-C_(y)H_(2y)—; R¹³ is C₁₋₆alkylcarbonyl; R¹⁴ isC₁₋₆alkoxycarbonyl; X is —O— or —S—; provided that when X is —O—, R¹⁷ ishydrogen or hydroxy, R¹⁸ is C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—,carboxy-C_(y)H_(2y)—, hydroxy-C_(y)H_(2y)—, C₁₋₆ alkylcarbonyl-O—, C₁₋₆alkylcarbonylamino, C₁₋₆alkylsulfonylamino or

or R¹⁷ and R¹⁸, together with the carbon atom, to which they areattached, form

when X is —S—, R¹⁷ is hydrogen, R¹⁸ is carboxy-C_(y)H_(2y)—; R¹⁹ isselected from aminocarbonyl; aminosulfonyl;C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkyl, which is unsubstituted orsubstituted by fluoro; C₁₋₆alkylaminosulfonyl; C₁₋₆alkylcarbonyl;C₁₋₆alkylsulfonyl and hydroxy-C_(x)H_(2x)-carbonyl; A is pyrazolyl oroxopyrazolyl, which is unsubstituted or substituted by C₁₋₆alkyl; x is1-6; y is 0-6; or pharmaceutically acceptable salts, or tautomerismisomers, or enantiomers, or diastereomers thereof.
 14. A compound ofclaim 1, wherein R¹ is methyl or ethyl; R² is phenyl, which is once ortwice or three times substituted by fluoro, chloro or bromo; R³ ishydrogen or methyl; R⁴ is selected from

wherein R¹⁷ is hydrogen or hydroxy; R¹⁸ is methoxycarbonyl,methoxycarbonylmethyl, methoxycarbonylmethyl(hydroxy), carboxy,carboxymethyl, hydroxy, hydroxymethyl, methylcarbonyl-O—,methylcarbonylamino or methylsulfonylamino; or R¹⁷ and R¹⁸, togetherwith the carbon atom, to which they are attached, form

R¹⁹ is aminocarbonyl, aminosulfonyl, methoxycarbonyl,ethoxycarbonylisopropyl, methyl, isopropyl, difluoroethyl,methylaminosulfonyl, methylcarbonyl, methylsulfonyl orhydroxymethylcarbonyl; A is pyrazolyl or oxopyrazolyl, which isunsubstituted or substituted by methyl; or pharmaceutically acceptablesalts, or tautomerism isomers, or enantiomers, or diastereomers thereof.15. A compound of claim 1 or pharmaceutically acceptable salts, ortautomerism isomers, or enantiomers, or diastereomers thereof, whereinR¹ is C₁₋₆alkyl; R² is phenyl, which is once or twice or three timessubstituted by halogen; R³ is hydrogen or C₁₋₆alkyl; R⁴ is selected from

X is —O— or —S—; provided that when X is —O—, R¹⁷ is hydrogen orhydroxy, R¹⁸ is C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—, carboxy-C_(y)H_(2y)—,hydroxy-C_(y)H_(2y)—, C₁₋₆ alkylcarbonyl-O—, C₁₋₆ alkylcarbonylamino,C₁₋₆alkylsulfonylamino or

or R¹⁷ and R¹⁸, together with the carbon atom, to which they areattached, form

when X is —S—, R¹⁷ is hydrogen, R¹⁸ is carboxy-C_(y)H_(2y)—; R¹⁹ isselected from aminocarbonyl; aminosulfonyl;C₁₋₆alkoxycarbonyl-C_(y)H_(2y)—; C₁₋₆alkyl, which is unsubstituted orsubstituted by fluoro; C₁₋₆alkylaminosulfonyl; C₁₋₆alkylcarbonyl;C₁₋₆alkylsulfonyl and hydroxy-C_(x)H_(2x)-carbonyl; A is pyrazolyl oroxopyrazolyl, which is unsubstituted or substituted by C₁₋₆alkyl; x is1-6; y is 0-6.
 16. A compound of claim 1, or pharmaceutically acceptablesalts, or tautomerism isomers, or enantiomers, or diastereomers thereof,wherein R¹ is methyl or ethyl; R² is phenyl, which is once or twice orthree times substituted by fluoro, chloro or bromo; R³ is hydrogen ormethyl; R⁴ is selected from

R¹⁷ is hydrogen or hydroxy; R¹⁸ is methoxycarbonyl,methoxycarbonylmethyl, methoxycarbonylmethyl(hydroxy), carboxy,carboxymethyl, hydroxy, hydroxymethyl, methylcarbonyl-O—,methylcarbonylamino or methylsulfonylamino; or R¹⁷ and R¹⁸, togetherwith the carbon atom, to which they are attached, form

R¹⁹ is aminocarbonyl, aminosulfonyl, methoxycarbonyl,ethoxycarbonylisopropyl, methyl, isopropyl, difluoroethyl,methylaminosulfonyl, methylcarbonyl, methylsulfonyl orhydroxymethylcarbonyl; A is pyrazolyl or oxopyrazolyl, which isunsubstituted or substituted by methyl.
 17. A compound of claim 1 orpharmaceutically acceptable salts, or tautomerism isomers, orenantiomers, or diastereomers thereof, wherein R¹ is C₁₋₆alkyl; R² isphenyl, which is once or twice or three times substituted by halogen; R³is hydrogen; R⁴ is


18. A compound of claim 1, or pharmaceutically acceptable salts, ortautomerism isomers, or enantiomers, or diastereomers thereof, whereinR¹ is methyl; R² is phenyl, which is once or twice or three timessubstituted by fluoro, chloro or bromo; R³ is hydrogen; R⁴ is


19. A compound of claim 1 to selected from9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid;9-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid;9-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid;9-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester;9-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-9-aza-bicyclo[3.3.1]nonane-7-carboxylicacid;8-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylicacid;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Acetoxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-hydroxy-7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2,2-difluoro-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methylsulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;9-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylicacid methyl ester;(R)-6-(7-Carbamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-sulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(1-ethoxycarbonyl-1-methyl-ethyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2-hydroxy-acetyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;7-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester;(S)-2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-5,5-difluoro-2-aza-bicyclo[2.2.2]octane-3-carboxylicacid;(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester;6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(7-carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(3-methyl-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5-methyl-3-oxo-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6)-en-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-10-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(2-methoxymethyl-azetidin-1-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(6-oxa-3-aza-bicyclo[3.1.1]hept-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-3-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3,6-diaza-bicyclo[3.2.1]octane-7-carboxylicacid;2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylicacid;(R)-6-(5-Acetyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-(7-Carboxymethyl-3-thia-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Diazirine-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-((1R,3R,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(9-oxa-3,4,11-triaza-tricyclo[5.3.1.0*2,6*]undeca-2(6),4-dien-11-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;2-[[(1R,5S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]aceticacid;2-[[(1R,5S)-9-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]aceticacid; Methyl(4R)-6-[(6-acetamido-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-[[8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]oxy]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylicacid; Methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-[[7-(2-hydroxyacetyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-[(7-carbamoyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-[(1R,5S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-endo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-endo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate;2-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-6-[[(1S,5R)-7-exo-ureido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-[(1R,5S,6S)-8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]aceticacid;Endo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Ethyl(4R)-6-[[(1S,5R)-7-endo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Ethyl(4R)-6-[[(1S,5R)-7-exo-acetamido-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;3-[(1S,5R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl]-2,2-dimethyl-3-oxo-propanoicacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-bromo-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;(1S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;(1R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;(1S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;(1R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-bromo-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(1S,5S,6R,7R)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(1R,5R,6S,7S)-9-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4,10-dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(4R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carrboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7,7-difluoro-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-arboxylicacid methyl ester; Methyl(4R)-4-(2-chloro-4-fluorophenyl)-6-[(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl]-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate;2-[(1R,3R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3R,5S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3S,5R)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3R,5S)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid or 2-[(1 S,3S,5R)-8-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4S)-4-(3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3R)-8-[[(4R)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid; 2-[(3S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxyc arbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid; Methyl (4R)-6-[(3-acetyl-3,8-diaz abicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7S)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(1R,5R,7S)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid or2-[(1S,5S,7R)-9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(1R,5R,7S)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid or2-[(1S,5S,7R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Endo-2-[9-[[(4R)-4-(2-bromophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Endo-2-[9-[[(4R)-4-(2-chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Endo-2-[9-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-1-hydroxy-2-oxo-ethyl)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-6,7-dihydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;7-amino-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid;7-amino-9-[[(4R)-4-(2,3-difluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid;7-amino-9-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(5,5-difluoro-3-azabicyclo[2.2.1]heptan-3-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-6-[[4-(acetamidomethyl)-5-oxa-2-azabicyclo[2.2.1]heptan-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-[(2,2,2-trifluoroacetyl)amino]-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;(1S,4R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid;(1R,4S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid;8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylicacid;(5S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylicacid; and(5R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylicacid.
 20. A compound of claim 1, selected from9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylicacid;8-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-8-aza-bicyclo[3.2.1]octane-6-carboxylicacid;(R)-6-(7-Carbamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-sulfamoyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-[7-(2-hydroxy-acetyl)-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl]-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester;(R)-4-(2-Bromo-4-fluoro-phenyl)-6-(7-carboxymethyl-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-12-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-10-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-(7-Acetylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(7-methanesulfonylamino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;2-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylicacid;6-(7-Carboxymethyl-3-thia-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-4-(2-Chloro-4-fluoro-phenyl)-6-(9-oxa-3,4,11-triaza-tricyclo[5.3.1.0*2,6*]undeca-2(6),4-dien-11-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;2-[[(1R,5S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]oxy]aceticacid;2-[[8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]oxy]aceticacid;8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-6-carboxylicacid; Methyl(4R)-4-(2-bromo-4-fluoro-phenyl)-6-[(7-carbamoyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-endo-(sulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[(1R,5S)-7-exo-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-[(1R,5S,6S)-8-[[(4R)-4-(2-bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;Exo-2-[(1S,5R)-9-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;(1S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;(1R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylicacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3R,5S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3S,5R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1R,3S,5S)-8-[[(4S)-4-(3,4-difluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(1S,3R,5R)-8-[[(4S)-4-(3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3R)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3S)-8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid; 2-[(3R)-8-[[(4R)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3S)-8-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid; 2-[(3R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(3S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl]aceticacid;2-[(7R)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid;2-[(7S)-9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[7-(2-ethoxy-2-oxo-ethyl)-7-(methanesulfonamido)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;(1S,4R)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid;(1R,4S)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylicacid;8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylicacid;2-[(7R)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid; and2-[(7S)-9-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]aceticacid.
 21. A process for the preparation of a compound of claim 1comprising the reaction of (a) a compound of formula (A)

with bridged amine in the presence of a base; (b) a compound of formula(B)

under chiral separation condition; wherein R¹ to R⁴ are defined as inclaim
 1. 22. A compound of claim 1 for use as therapeutically activesubstance.
 23. A pharmaceutical composition comprising a compound ofclaims 1 and a therapeutically inert carrier.
 24. A compound accordingto any one of claims 1, when manufactured according to a process ofclaim
 21. 25. A method for the treatment or prophylaxis of hepatitis Bvirus infection, which method comprises administering an effectiveamount of a compound of claim 1.